US8440677B2 - Atropisomers of 2-purinyl-3-tolyl-quinazolinone derivatives and methods of use - Google Patents

Atropisomers of 2-purinyl-3-tolyl-quinazolinone derivatives and methods of use Download PDF

Info

Publication number
US8440677B2
US8440677B2 US12/731,089 US73108910A US8440677B2 US 8440677 B2 US8440677 B2 US 8440677B2 US 73108910 A US73108910 A US 73108910A US 8440677 B2 US8440677 B2 US 8440677B2
Authority
US
United States
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
formula
optically active
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related, expires
Application number
US12/731,089
Other languages
English (en)
Other versions
US20100249155A1 (en
Inventor
Jerry B. Evarts
Roger G. Ulrich
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gilead Calistoga LLC
Original Assignee
Gilead Calistoga LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=42289320&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US8440677(B2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Gilead Calistoga LLC filed Critical Gilead Calistoga LLC
Priority to US12/731,089 priority Critical patent/US8440677B2/en
Assigned to CALISTOGA PHARMACEUTICALS, INC. reassignment CALISTOGA PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: EVARTS, JERRY B., ULRICH, ROGER G.
Publication of US20100249155A1 publication Critical patent/US20100249155A1/en
Assigned to GILEAD CALISTOGA LLC reassignment GILEAD CALISTOGA LLC CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: CALISTOGA PHARMACEUTICALS, INC.
Application granted granted Critical
Publication of US8440677B2 publication Critical patent/US8440677B2/en
Expired - Fee Related legal-status Critical Current
Adjusted expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the invention is in the field of therapeutics and medicinal chemistry for the treatment of inflammatory conditions and/or oncology disorders using compounds that inhibit phosphatidylinositol-3,4,5-triphosphate kinase ⁇ (PI3K ⁇ ) enzymes in vivo.
  • the invention concerns compounds, compositions, and methods of treatment of inflammatory conditions and/or oncology disorders with enantiomerically enriched 2-((6-amino-9H-purin-9-yl)methyl)-5-methyl-3-o-tolylquinazolin-4(3H)-one.
  • PI 3-kinase phosphatidylinositol 3-kinase
  • PI3K phosphatidylinositol 3-kinase
  • PI 3-kinases phosphatidylinositol 3-kinases
  • Inflammatory responses are notably associated with the influx of leukocytes and/or leukocyte chemotaxis. Inflammatory responses may result from infection with pathogenic organisms and viruses, noninfectious means such as trauma or reperfusion following myocardial infarction or stroke, immune responses to foreign antigens, and autoimmune diseases. Leukocytes provide a first line of immune defense against many common microorganisms.
  • compounds that express relatively high levels of p110 ⁇ may be useful for treating mainly hematologic cancers.
  • the p110 ⁇ isoform of PI3K may also play a role in PI3K-mediated signaling in certain cancers, such as solid tumors.
  • the invention relates to selective PI3K ⁇ inhibitors and methods to treat inflammatory conditions and cancers with compounds that are selective PI3K ⁇ inhibitors.
  • compounds of the invention exist as separable atropisomers and the invention provides separated atropisomers having unexpected advantages over mixtures of atropisomers for use in treatment of inflammation.
  • the compounds, compositions, and methods of the invention are therapeutically beneficial in treating inflammatory conditions.
  • the invention provides an optically active compound comprising an atropisomer of formula 1(S)
  • optically active atropisomer obtained consists predominantly of the first isomer to elute from the column.
  • the optically active atropisomer obtained consists of the compound of formula 1(S) substantially free of the compound of formula 1(R).
  • the invention provides an optically active atropisomer obtained by chiral chromatographic separation of a racemic of formula 1
  • optically active atropisomer obtained consists predominantly of the second isomer to elute from the column.
  • FIG. 1 shows a synthetic scheme of the preparation of racemic compound 1.
  • FIG. 2 shows HPLC traces of injected compound, 1, containing resolved atropisomers on normal phase ( FIG. 2A ) or reverse phase ( FIG. 2B ) chiral columns.
  • FIG. 3 shows HPLC traces of resolved injected compound, 1, prior to preparatory chromatographic separation ( FIG. 3A ), and isolated atropisomers peak 1 ( FIG. 3B ), 1(S), and peak 2 ( FIG. 3C ), 1(R), after separation using a normal phase column method.
  • FIG. 4 shows solubility data of compound 1 and the resolved atropisomers, 1(S) and 1(R), in a series of aqueous solvents.
  • FIG. 5 shows the differences in p110 activity of different isoforms between racemic compound 1 and the atropisomers 1(S) and 1(R) in biochemical ( FIG. 5A ) and cell-based assays ( FIG. 5B ).
  • FIG. 6 shows the plasma concentration of atropisomers 1(S) and 1(R) in rats after oral dosing with racemic compound 1.
  • FIG. 7 shows the plasma concentration of atropisomers 1(S) and 1(R) in dogs after oral dosing with racemic compound 1.
  • FIG. 9 shows a comparison of the plasma concentration of atropisomers 1(S) and 1(R) in rats subjects after either i.v. ( FIG. 9A ) or oral ( FIG. 9B ) dosing with compounds 1(S) or 1(R).
  • FIG. 10 shows a comparison of the plasma concentration of atropisomers 1(S) and 1(R) in human subjects after a single oral dose of 100 mg ( FIG. 10A , 10 B) or 10 mg ( FIG. 10C , 10 D) of 1(S) or 1(R).
  • FIG. 11 shows a comparison of plasma concentration of radiolabeled 14 C atropisomers 1(S) and 1(R) in human subjects over 120 hours during daily administration of 25 mg of racemic compound 1.
  • FIG. 12 shows LC-MS analytical traces of metabolites in rat urine after administration of atropisomer 1(S) ( FIG. 12A ) or atropisomer 1(R) ( FIG. 12B ).
  • FIG. 13 shows analytical traces of metabolites in human plasma after administration of atropisomer 1(S) or atropisomer 1(R), tested 1 hour ( FIG. 13A , 13 B) or 72 hours ( FIG. 13C , 13 D) after oral administration.
  • FIG. 15 shows a graph of anti-collagen antibody levels in rat after dosing the subjects with vehicle, 1(S) or methotrexate.
  • FIG. 16 shows a graph of X-ray score from a radiographic assessment of rats treated with either vehicle, 1(S), or methotrexate.
  • FIGS. 17A-D shows images from histopathology data from subjects treated with vehicle, 1(S), or methotrexate.
  • racemic mixture A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate.
  • racemic mixture and “racemate” refer to an equimolar mixture of two enantiomeric species, which is devoid of optical activity.
  • chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • enantiomers refers to two stereoisomers of a compound.
  • atropisomers refers to conformational stereoisomers which occur when rotation about a single bond in the molecule is prevented, or greatly slowed, as a result of steric interactions with other parts of the molecule and the substituents at both ends of the single bond are asymmetrical, i.e., they do not require a stereocenter. Where the rotational barrier about the single bond is high enough, and interconversion between conformations is slow enough, separation and isolation of the isomeric species may be permitted. Atropisomers are enantiomers without a single asymmetric atom.
  • the energy barrier to thermal racemization of atropisomers may be determined by the steric hindrance to free rotation of one or more bonds forming a chiral axis. Certain biaryl compounds exhibit atropisomerism where rotation around an interannular bond lacking C2 symmetry is restricted.
  • the free energy barrier for isomerization (enantiomerization) is a measure of the stability of the interannular bond with respect to rotation. Optical and thermal excitation can promote racemization of such isomers, dependent on electronic and steric factors.
  • Ortho-substituted biphenyl compounds may exhibit this type of conformational, rotational isomerism.
  • Such biphenyls are enantiomeric, chiral atropisomers where the sp2-sp2 carbon-carbon, interannular bond between the phenyl rings has a sufficiently high energy barrier to prevent free rotation, and where substituents X ⁇ Y and U ⁇ V render the molecule asymmetric.
  • Atropisomerism is defined to exist where the isomers have a half-life, t 1/2 , of at least 1,000 seconds, which is a free energy barrier of 22.3 kcal mol ⁇ 1 (93.3 kJ mol ⁇ 1 ) at 300K (Oki, M. “Recent Advances in Atropisomerism,” Topics in Stereochemistry (1983) 14:1).
  • Bold lines and dashed lines in the figures shown above indicate those moieties, or portions of the molecule, which are sterically restricted due to a rotational energy barrier.
  • Bolded moieties exist orthogonally above the plane of the page, and dashed moieties exist orthogonally below the plane of the page.
  • the ‘flat’ part of the molecule (the left ring in each of the two depicted biphenyls) is in the plane of the page.
  • the S designation is assigned by applying sequence rules to name compounds with axial chirality. These rules are applied to primarily the ortho substituents of the biphenyl ring.
  • the two linked rings may be represented by a horizontal and a vertical line.
  • the lines represent the two orthogonal rings; and the ends of the lines represent the substituents at the four ortho positions of the two linked rings. These lines thus join each pair of ortho substituents.
  • the two groups on the nearest ring (the ‘front’ line) take precedence over the two far groups.
  • substituents are assigned priorities using the same priority rules used for describing R and S enantiomers of a chiral center.
  • the perspective is viewing the molecule from the left side, looking down the axis from 1 to 1′.
  • the near ring is represented by the bold vertical line connecting —OCH 3 and H, which are numbered 1 and 2, respectively, since —OCH 3 has a higher priority over H.
  • the horizontal line represents the ring containing NO 2 and CO 2 H, which are numbered 3 and 4, respectively, based on their priority.
  • the sequence 1->2->3 reveals the configurational descriptor, which in this example is S, because following the numerical sequence in order requires going counter clockwise around the center of the diagram.
  • the numbered substituents are then taken in sequence by traveling either clockwise or counterclockwise around the point where the two lines intersect. If the path around the center point had been clockwise, the atropisomer would be designated R, just as it is for enantiomers of a stereocenter.
  • compound 3 which is representative of a portion of the some of the compounds herein, such as compound 1(S), is assigned an absolute configuration of S as shown below.
  • the atropisomers are preferably sufficiently stable to be stored and used without substantial thermal interconversion.
  • the atropisomers have a half-life of greater than 1 week when in solid form at room temperature.
  • the compound of formula 1,2-((6-amino-9H-purin-9-yl)methyl)-5-methyl-3-o-tolylquinazolin-4(3H)-one has two atropisomers represented by formulas 1(S) and 1(R).
  • Formula 1 represents a mixture of equal amounts of the two atropisomers 1(S) and 1(R).
  • Formula 1(R) is the corresponding enantiomer of formula 1(S) and vice versa.
  • an atropisomer “substantially free” of its corresponding enantiomer means that the composition contains at least 90% by weight of one atropisomer, and 10% by weight or less of its stereoisomeric atropisomer. In some embodiments, the composition contains at least 95% by weight of one atropisomer and 5% by weight or less of its stereoisomer. In some embodiments, the composition contains at least 98% by weight of one atropisomer and 2% by weight or less of its stereoisomer. Alternatively, the relative amounts of the predominant isomer and any of the minor enantiomer is at least 9:1, or at least 19:1, or at least 98:2.
  • the composition contains at least 99% by weight of one atropisomer and 1% by weight or less of its stereoisomer. In some embodiments, the composition contains at least 99.5% by weight of one atropisomer and 0.5% by weight or less of its stereoisomer.
  • the atropisomeric compounds of the invention are typically solid materials, and are optionally purified to greater than about 90% purity, even if they exist as a mixture of atropisomers.
  • the atropisomeric compound of the invention is substantially free of proteinaceous materials, or any materials having a molecular weight over about 1000 amu. Typically, they are at least 90% pure (chemically pure, regardless of optical purity), and preferably at least 95% chemically pure.
  • compositions and methods of the invention utilize an optically active form of the compounds described, meaning in each instance, the compound is optically active and contains predominantly the S-stereoisomer, such as 1(S), although it may contain the R-stereoisomer, such as 1(R), as a minor component. In other embodiments, the compound is optically active and contains predominantly the R-stereoisomer, such as 1(R), although it may contain the S-stereoisomer, such as 1(S), as a minor component.
  • the dosage refers to the weight of the compound including each stereoisomer that is present.
  • a dosage of 100 mg of compound 1(S) as used herein refers to the weight of the mixture of stereoisomers rather than the weight of the S-stereoisomer specifically. It could, for example, refer to 100 mg of a 9:1 mixture of S and R stereoisomers, which would contain about 90 mg of the S stereoisomer, or to 100 mg of a 19:1 mixture of S and R stereoisomers, which would contain about 95 mg of the S stereoisomer.
  • the compound is preferably a non-racemic mixture wherein the S isomer is the major component of the mixture.
  • such mixture will contain no more than about 10% of the R isomer, meaning the ratio of S to R isomers is at least about 9:1, and preferably less than 5% of the R-isomer, meaning the ratio of S to R enantiomers is at least about 19:1.
  • the compound has less than 2% R enantiomer, meaning it has an enantiomeric excess of at least about 96%.
  • the compound has an enantiomeric excess of at least 98%.
  • the compound has an enantiomeric excess of at least 99%.
  • the compound is preferably a non-racemic mixture wherein the R isomer is the major component of the mixture.
  • the R isomer is the major component of the mixture.
  • such mixture will contain no more than about 10% of the S isomer, meaning the ratio of R to S isomers is at least about 9:1, and preferably less than 5% of the S-isomer, meaning the ratio of R to S enantiomers is at least about 19:1.
  • the compound has less than 2% S enantiomer, meaning it has an enantiomeric excess of at least about 96%.
  • the compound has an enantiomeric excess of at least 98%.
  • the compound has an enantiomeric excess of at least 99%.
  • An atropisomer which is present “in excess” of its corresponding enantiomer or an “enantioenriched mixture” means that the atropisomer is present in an amount greater than its enantiomer, making the atropisomer mixture optically active. Typically this means the compound present “in excess” predominates by at least a 60/40 ratio over its enantiomer.
  • the invention relates to selective PI3K ⁇ inhibitors and methods to treat inflammatory conditions and/or oncology disorders with compounds that are selective PI3K ⁇ inhibitors.
  • compounds of the invention exist as separable atropisomers and the invention provides separated atropisomers having unexpected advantages over mixtures of atropisomers for use in treatment of inflammation.
  • the compounds, compositions, and methods of the invention are therapeutically beneficial in treating inflammatory conditions.
  • the invention provides an optically active compound comprising an atropisomer of formula 1(S)
  • the atropisomer of formula 1(S) is substantially free of its corresponding atropisomer of formula 1(R).
  • the invention provides an optically active compound comprising an atropisomer of formula 1(R)
  • the atropisomer of formula 1(R) is substantially free of its corresponding atropisomer of formula 1(S).
  • the invention provides a pharmaceutical composition comprising any of the optically active compounds described herein, and at least one pharmaceutically acceptable excipient.
  • the optically active compound is 1(S) or 1(R). In other embodiments, the optically active compound is 1(S). In yet other embodiments, the optically active compound is 1(R).
  • the composition comprises a therapeutically effective amount of the optically active atropisomer for the treatment of a condition, wherein the condition is characterized by inflammation.
  • the condition is selected from the group consisting of chronic inflammatory diseases, tissue or organ transplant rejections, graft versus host disease (GVHD), multiple organ injury syndromes, acute glomerulonephritis, reactive arthritis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), cystic fibrosis, adult respiratory distress syndrome (ARDS), ischemic-reperfusion injury, stroke, rheumatoid arthritis (RA), osteoarthritis (OA), asthma, allergic rhinitis, diabetes, lupus nephritis, Crohn's disease, ulcerative colitis, necrotizing enterocolitis, pancreatitis, Pneumocystis carinii pneumonia (PCP), inflammatory bowel disease (IBD), severe acute respiratory syndrome (SARS), sepsis,
  • GVHD
  • the invention provides a method of treating a condition in a mammal, wherein the condition is characterized by inflammation.
  • the condition is selected from the group consisting of chronic inflammatory diseases, tissue or organ transplant rejections, graft versus host disease (GVHD), multiple organ injury syndromes, acute glomerulonephritis, reactive arthritis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), cystic fibrosis, adult respiratory distress syndrome (ARDS), ischemic-reperfusion injury, stroke, rheumatoid arthritis (RA), osteoarthritis (OA), asthma, allergic rhinitis, diabetes, lupus nephritis, Crohn's disease, ulcerative colitis, necrotizing enterocolitis, pancreatitis, Pneumocystis carinii pneumonia (PCP), inflammatory bowel disease (IBD), severe acute respiratory syndrome (SARS), sepsis, community acquired pneumonia (CAP), multiple s
  • GVHD
  • the optically active compound is represented by formula 1(S). In other embodiments, the optically active compound is represented by formula 1(R).
  • the mammal is one identified as in need of treatment for the disorder. In some embodiments, the mammal is one at risk of the condition and the compound or composition is administered to reduce or prevent the occurrence of inflammation.
  • a method of the present invention can be employed to treat subjects therapeutically or prophylactically who have or can be subject to an inflammatory condition.
  • the invention provides a method of treating a condition in a mammal, wherein the condition is selected from the group consisting of allergic rhinitis, asthma, atopic dermatitis, chronic obstructive pulmonary disease (COPD), multiple sclerosis (MS), rheumatoid arthritis (RA), and diabetes, which comprises administering to a mammal in need thereof a therapeutically effective amount of the atropisomer 1(S) or a pharmaceutically acceptable salt thereof.
  • COPD chronic obstructive pulmonary disease
  • MS multiple sclerosis
  • RA rheumatoid arthritis
  • the invention provides a method of treating a condition in a mammal, wherein the condition is selected from the group consisting of allergic rhinitis, asthma, atopic dermatitis, chronic obstructive pulmonary disease (COPD), multiple sclerosis (MS), rheumatoid arthritis (RA), and diabetes, which comprises administering to a mammal in need thereof a therapeutically effective amount of the atropisomer 1(S) or a pharmaceutically acceptable salt thereof, wherein the atropisomer is substantially free of its corresponding enantiomer.
  • COPD chronic obstructive pulmonary disease
  • MS multiple sclerosis
  • RA rheumatoid arthritis
  • the invention provides a method of treating a condition in a mammal, wherein the condition is selected from the group consisting of allergic rhinitis, asthma, atopic dermatitis, chronic obstructive pulmonary disease (COPD), multiple sclerosis (MS), rheumatoid arthritis (RA), and diabetes, which comprises administering to a mammal in need thereof a therapeutically effective amount of the atropisomer 1(S) or a pharmaceutically acceptable salt thereof, wherein the atropisomer is substantially free of its corresponding enantiomer and has an enantiomeric excess of at least 90%.
  • COPD chronic obstructive pulmonary disease
  • MS multiple sclerosis
  • RA rheumatoid arthritis
  • diabetes which comprises administering to a mammal in need thereof a therapeutically effective amount of the atropisomer 1(S) or a pharmaceutically acceptable salt thereof, wherein the atropisomer is substantially free of its corresponding enantiomer and has an
  • the invention provides a method of treating a condition in a mammal, wherein the condition is selected from the group consisting of allergic rhinitis, asthma, atopic dermatitis, chronic obstructive pulmonary disease (COPD), multiple sclerosis (MS), rheumatoid arthritis (RA), and diabetes, which comprises administering to a mammal in need thereof a therapeutically effective amount of the atropisomer 1(S) or a pharmaceutically acceptable salt thereof, wherein the atropisomer is substantially free of its corresponding enantiomer and has an enantiomeric excess of at least 98%.
  • COPD chronic obstructive pulmonary disease
  • MS multiple sclerosis
  • RA rheumatoid arthritis
  • diabetes which comprises administering to a mammal in need thereof a therapeutically effective amount of the atropisomer 1(S) or a pharmaceutically acceptable salt thereof, wherein the atropisomer is substantially free of its corresponding enantiomer and has an
  • the invention provides a method of treating a condition in a mammal, wherein the condition is selected from the group consisting of allergic rhinitis, asthma, atopic dermatitis, chronic obstructive pulmonary disease (COPD), multiple sclerosis (MS), rheumatoid arthritis (RA), and diabetes, which comprises administering to a mammal in need thereof a therapeutically effective amount of the atropisomer 1(S) or a pharmaceutically acceptable salt thereof, wherein the atropisomer is substantially free of its corresponding enantiomer and has an enantiomeric excess of at least 99%.
  • COPD chronic obstructive pulmonary disease
  • MS multiple sclerosis
  • RA rheumatoid arthritis
  • diabetes which comprises administering to a mammal in need thereof a therapeutically effective amount of the atropisomer 1(S) or a pharmaceutically acceptable salt thereof, wherein the atropisomer is substantially free of its corresponding enantiomer and has an
  • the invention provides a method of treating allergic rhinitis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of optically active atropisomer 1(S) or a pharmaceutically acceptable salt thereof, wherein the atropisomer is substantially free of its corresponding enantiomer.
  • the invention provides a method of treating asthma in a human, which comprises administering to a human in need thereof a therapeutically effective amount of optically active atropisomer 1(S) or a pharmaceutically acceptable salt thereof, wherein the atropisomer is substantially free of its corresponding enantiomer.
  • the invention provides a method of treating chronic obstructive pulmonary disease (COPD) in a human, which comprises administering to a human in need thereof a therapeutically effective amount of optically active atropisomer 1(S) or a pharmaceutically acceptable salt thereof, wherein the atropisomer is substantially free of its corresponding enantiomer.
  • COPD chronic obstructive pulmonary disease
  • the invention provides a method of treating multiple sclerosis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of optically active atropisomer 1(S) or a pharmaceutically acceptable salt thereof, wherein the atropisomer is substantially free of its corresponding enantiomer.
  • the invention provides a method of treating rheumatoid arthritis in a human, which comprises administering to a human in need thereof a therapeutically effective amount of optically active atropisomer 1(S) or a pharmaceutically acceptable salt thereof, wherein the atropisomer is substantially free of its corresponding enantiomer.
  • the invention provides a method of treating diabetes in a human, which comprises administering to a human in need thereof a therapeutically effective amount of optically active atropisomer 1(S) or a pharmaceutically acceptable salt thereof, wherein the atropisomer is substantially free of its corresponding enantiomer.
  • the invention provides a method of treating a condition in a human, wherein the condition is selected from the group consisting of allergic rhinitis, asthma, atopic dermatitis, chronic obstructive pulmonary disease (COPD), multiple sclerosis (MS), rheumatoid arthritis (RA), and diabetes, which comprises administering to a human in need thereof a therapeutically effective amount of an optically active atropisomer having the formula
  • inflammatory conditions include but are not limited to arthritic diseases such as rheumatoid arthritis (RA), osteoarthritis (OA), gouty arthritis, spondylitis, and reactive arthritis; Behçet's syndrome; sepsis; septic shock; endotoxic shock; gram negative sepsis; gram positive sepsis; toxic shock syndrome; multiple organ injury syndrome secondary to septicemia, trauma, or hemorrhage; ophthalmic disorders including but not limited to allergic conjunctivitis, vernal conjunctivitis, uveitis, and thyroid-associated opthalmopathy; eosinophilic granuloma; pulmonary or respiratory conditions including but not limited to asthma, chronic bronchitis, allergic rhinitis, adult respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), chronic pulmonary inflammatory diseases (e.g., chronic obstructive pulmonary disease), silicosis, pulmonary sarcoidosis, ple
  • the condition is selected from the group consisting of allergic rhinitis, asthma, atopic dermatitis, chronic obstructive pulmonary disease (COPD), multiple sclerosis (MS), rheumatoid arthritis (RA), and diabetes.
  • diabetes is type I diabetes or type II diabetes.
  • the invention provides a method of treating a condition in a mammal, wherein the condition is cancer, which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound described herein.
  • the cancer is a hematological malignancy.
  • the hematological malignancy is leukemia, lymphoma, or multiple myeloma.
  • the cancer is a solid tumor.
  • lymphoma is a mature (peripheral) B-cell neoplasm.
  • the mature B-cell neoplasm is selected from the group consisting of B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma; B-cell prolymphocytic leukemia; Lymphoplasmacytic lymphoma; Marginal zone lymphoma, such as Splenic marginal zone B-cell lymphoma (+/ ⁇ villous lymphocytes), Nodal marginal zone lymphoma (+/ ⁇ monocytoid B-cells), and Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type; Hairy cell leukemia; Plasma cell myeloma/plasmacytoma; Follicular lymphoma, follicle center; Mantle cell lymphoma; Diffuse large cell B-cell lymphoma (including Mediastinal large B-cell lymphom
  • lymphoma is selected from the group consisting of multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldenstrom's macroglobulinemia (WM) or B-cell lymphoma and diffuse large B-cell lymphoma (DLBCL).
  • MM multiple myeloma
  • NHL non-Hodgkin's lymphoma
  • MCL mantle cell lymphoma
  • follicular lymphoma follicular lymphoma
  • Waldenstrom's macroglobulinemia WM
  • B-cell lymphoma diffuse large B-cell lymphoma
  • leukemia is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and small lymphocytic lymphoma (SLL).
  • ALL acute lymphocytic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • Acute lymphocytic leukemia is also known as acute lymphoblastic leukemia and may be used interchangeably herein. Both terms describe a type of cancer that starts from the white blood cells, lymphocytes, in the bone marrow.
  • the hematological malignancy is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL).
  • ALL acute lymphocytic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • MM multiple myeloma
  • NHL non-Hodgkin lymphoma
  • NHL non-Hodgkin lymphoma
  • the invention provides a method of treating a hematological malignancy in a mammal, which comprises administering to a mammal in need thereof a therapeutically effective amount of optically active atropisomer 1(S) or a pharmaceutically acceptable salt thereof.
  • the invention provides a method of treating a condition in a mammal, wherein the condition is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), which comprises administering to a mammal in need thereof a therapeutically effective amount of optically active atropisomer 1(S) or a pharmaceutically acceptable salt thereof.
  • ALL acute lymphocytic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • MM multiple myeloma
  • NHS non-Hodgkin lymphoma
  • the invention provides a method of treating cancer in a human, wherein the cancer is leukemia, lymphoma, or multiple myeloma, which comprises administering to a human in need thereof a therapeutically effective amount of an optically active atropisomer having the formula
  • the invention provides a method of treating a condition in a mammal, wherein the cancer is a solid tumor, which comprises administering to a mammal in need thereof a therapeutically effective amount of the optically active atropisomer 1(S) or a pharmaceutically acceptable salt thereof.
  • the cancer is breast, lung, colon, or prostate cancer.
  • the invention provides methods to treat a solid tumor that is associated with abnormal or undesirable cellular signaling activity mediated by PI3K ⁇ .
  • a solid tumor is selected from the group consisting of pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; renal cancer, including, e.g., metastatic renal cell carcinoma; hepatocellular cancer; lung cancer, including, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung; ovarian cancer, including, e.g., progressive epithelial or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, e.g., squamous cell carcinoma of the head and neck; melanoma;
  • NSCLC non-small cell lung
  • the cancer is breast, ovarian, lung, colon, or prostate cancer.
  • the mammal is a human.
  • racemic mixture of formula 1 is separated using a normal phase chiral column, and two peaks, A and B, are resolved, wherein peak A and peak B represent the atropisomers, 1(S) and 1(R), respectively,
  • the optically active atropisomer obtained consists predominantly of the second isomer to elute from the column
  • the optically active atropisomer obtained consists predominantly of the compound of formula 1(S) substantially free of the compound of formula 1(R).
  • the predominant optically active atropisomer obtained consists predominantly of the compound of formula 1(R) substantially free of the compound of formula 1(S).
  • the compound of the invention is separated using a chiral chromatographic column.
  • the chiral column has a normal phase.
  • the chiral column has a reverse phase.
  • the atropisomers of formula 1 were separated by normal phase HPLC methods resulting in two resolved peaks. See Example 2 and FIG. 2A for column and solvent conditions.
  • the peak to elute first at 7.4 minutes has been labeled 1(S) and the second peak to elute at 12.3 minutes has been labeled 1(R).
  • the absolute configuration of each isolated compound has been elucidated from x-ray crystallographic data.
  • the first peak to elute has been assigned the S configuration, shown as compound 1(S), and the second peak to elute has been assigned the R configuration, shown as compound 1(R).
  • the elution order of the peaks is reversed when a reverse phase column is used, as described in Example 2.
  • the tagged racemic mixture or separated atropisomers were administered to rats, dogs, and human subjects through oral and i.v. routes.
  • the compounds were dissolved in PEG 100 such that any difference in dissolution rates would not play a role in the pharmacokinetic profile of the compounds.
  • Modest solubility differences between 1(S) and 1(R) were observed in a variety of aqueous solutions as summarized in FIG. 4 .
  • blood plasma of the subjects were sampled over time and evaluated by analytical HPLC methods developed to identify and measure concentrations of compound 1(S) or 1(R) present in the sample. It was observed that the most abundant isomer measured in the plasma is compound 1(S), which accounts for 70-80% of exposure to the subject.
  • FIG. 6 shows the blood plasma concentration of 1(S) and 1(R) over 24 hours after a single 50 mg/kg dose of racemic 1 was orally administered to female rats.
  • concentration of 1(S) steadily increases in the blood and 8 hours after dosing the average concentration of 1(R) is approximately one-fourth the concentration of 1(R).
  • FIG. 7 shows the blood plasma concentration of 1(S) and 1(R) over 24 hours after a single 50 mg/kg dose of racemic 1 was orally administered to female dogs. In approximately 1 hour after dosing the maximum concentration of 1(S) and 1(R) is reached. At that point, the concentration of 1(R) is less than half the concentration of 1(S). This demonstrates an in vivo difference in exposure between 1(S) and 1(R) when orally administered to dogs, wherein the subject has increased exposure to 1(S) than 1(R). These large differences in pharmacokinetic behavior were not predictable.
  • FIG. 8 shows the blood plasma concentration of 1(S) and 1(R) over 72 hours after a single 100 mg dose of racemic 1 was orally administered to human subjects.
  • the maximum concentration of 1(S) and 1(R) is reached.
  • the concentration of 1(R) is less than half the concentration of compound 1(S), which accounts for approximately 70% of the exposure in the animal.
  • the concentrations of both compounds steadily decrease thereafter, at 72 hours post-dosing, the concentration of 1(S) is well over 10 times the concentration of 1(R).
  • the half-life of 1(S) is past the 72 hour time point.
  • the half-life of 1(S) of several days in humans is greater than the half-life in dogs.
  • the long half-life of 1(S) in humans allows for a lower dosage of administration.
  • Reduced administrative dosages may also reduce, if any, undesired side-effects of the compound in the subject and provides an advantage over administration of the racemic mixture, or over 1(R).
  • FIG. 9 shows the blood plasma concentration of 1(S) and 1(R) over a period of 24 hours after a single dose of 1(S) or 1(R) (1.5 mg/kg) administered either via a single bolus i.v. dose ( FIG. 9A ) or an oral dose ( FIG. 9B ) to female rat subjects.
  • the exposure level of 1(R) is approximately one-fifth the concentration of 1(S).
  • the concentration of both compounds is very low and within experimental error.
  • the concentration of 1(S) in blood plasma of rats that were orally administered the compounds was shown to greatly exceed the concentration of 1(R) at the 12 hour time point. This demonstrates an in vivo difference in exposure between 1(S) and 1(R) when either intravenously or orally administered to rats, wherein the subject has increased exposure to 1(S) relative to 1(R).
  • Table 1 summarizes the major pharmacokinetic parameters of 1(S) and 1(R) following a single bolus i.v. dose in female Sprague Dawley (SD) rats. Most notable is the half life of compound 1(R), which is about 2.8 times greater than the half life of either atropisomer 1(S) or the racemic mixture 1.
  • Compound 1(R) has a volume of the terminal phase (Vz) value of 14,833 mL/kg, which is about 2.6 times greater than the Vz for either 1(S) or the racemic mixture.
  • FIGS. 10A and 10B show graphs of the blood plasma concentration of 1(S) and 1(R) plotted against a period of 72 hours after administration of a single, oral dose of 100 mg of the atropisomers.
  • the maximum concentration of 1(S) is over 2 times as great as the maximum concentration for 1(R).
  • the concentration of the compounds in the blood plasma decreases over the 72 hour period, the difference in concentration of the two compounds maintained, if not further broadened.
  • This difference in compound concentration in the blood appears to broaden because compound 1(S) decreases more gradually over time whereas compound 1(R) appears to be removed from the blood relatively more quickly.
  • the maximum blood plasma concentration of compound 1(S) is still about double the maximum concentration of compound 1(R), see FIGS. 10C and 10D .
  • FIG. 11 depicts the concentration of 14 C radiolabeled compound 1(S) and 1(R) in total blood plasma. Subjects were dosed with 25 mg of a racemic mixture of 1(S) and 1(R) each day for 7 days. On day 4, the dose was ‘spiked’ with 40 nCi of labeled 1(S) or labeled 1(R). (Total dosage was still 25 mg of the racemic mixture, since the amount of labeled material was less than 0.1 mg so it did not materially affect the dosage.) FIG. 11 shows the pharmacokinetic profile for total radiolabeled material starting when the spiked material was administered on day 4, and continuing for several days thereafter.
  • both compounds in this test quickly reached their maximum concentration values and began a steady decline of concentration in the bloodstream.
  • the amount of 1(R), about 500 neq/mL is about one-fourth the concentration of 1(S), which is about 2,000 neq/mL.
  • the more rapid decline of 1(R) in the blood compared to 1(S) is further evident at 50 hours from dosing, wherein the blood plasma concentration of compound 1(S) is between 500 to 1,000 neq/mL compared to concentration of 1(R) which is about 10-50 neq/mL.
  • the concentration of 1(R) decreases more rapidly than the concentration of 1(S) as shown by the sharper slope of the 1(R) curve compared to the more gradual and gentle slope of 1(S) in FIG. 11 .
  • Table 2 summarizes the half-life, C max and AUC values in human subjects for compounds 1(S) and 1(R) based on the data in FIG. 11 .
  • compound 1(S) has a half-life 6 times as long as the half-life of 1(R), which has a half-life of under 11 hours.
  • the C max value for 1(S) is twice as long as that of 1(R), and the AUC value for 1(S) is over 4 times as that of 1(R).
  • 1(R) is preferentially eliminated in urine.
  • 1(R) has been shown to have a larger volume of distribution, V z , and has a greater rate of excretion and lower rate of absorption than 1(S).
  • 1(R) may also be metabolized faster than 1(S). Regardless of the reasons, 1(R) is far less available in plasma (circulation) than 1(S) when administered orally, and 1(S) provides a far more stable exposure to the drug and lower exposure to metabolites.
  • FIGS. 12A and 12B show the LC-MS analysis results of the metabolites found in the urine. Rats which were exposed to 1(S) produced mainly one compound represented by a peak at 13.4 minutes and a second compound represented by a much smaller peak at 14.5 minutes.
  • the analytical traces of urine from rats which were administered compound 1(R) are characterized by three main peaks at 13.5, 14.4, and 15.6 minutes, and a small peak at minute 12.1. This demonstrates that compound 1(R) is metabolized in vivo to produce more metabolic products compared to compound 1(S) and suggests that the two atropisomers are not metabolized by the body in exactly the same way.
  • the metabolite level is nearly as large as the level of compound 1(R), even just one hour after administration of 1(R).
  • compound 1(S) results in less metabolite formation than compound 1(R) in human plasma, and remains largely unmodified after 1 hr.
  • the amount of metabolites formed from 1(S) is still less than the amount of the parent compound 1(S), FIG. 13C . It appears that a small amount of 1(R) is present at this point in time, suggesting that some interconversion of 1(S) to 1(R) may occur in vivo.
  • compounds, compositions, and methods of the invention comprise 1(R).
  • compounds, compositions, and methods of the invention comprise 1(S).
  • Chromatographic columns may be characterized as ‘normal phase’ or ‘reverse phase’.
  • normal phase columns have a polar stationary phase and reverse phase columns have a non-polar stationary phase.
  • Suitable chiral columns can be purchased prepackaged or can be packed by one of ordinary skill in the art.
  • Suitable chiral columns include chiral CHIRALPAK®IA, IB, AD-H, AS, AD-RH, AS-RH and IC columns as well as CHIRALCEL®OD-H, OB-H, OF, OG, OJ-RH and OJ which can be purchased from Chiral Technologies Inc., 730 Springdale Drive, PO Box 564, Exton, Pa. 19341.
  • the packing composition for CHIRALPAK® IA columns is amylose tris(3,5-dimethylphenylcarbamate) immobilized on 5 ⁇ M silica-gel.
  • the packing material can also be purchased in different bead sizes. Suitable bead sizes for preparative separations are about 20 microns in diameter or less. Suitable bead sizes for analytical separation are about 10 microns in diameter or less.
  • the appropriate mobile phase used in an HPLC method can be selected from various combinations and ratios of solvents.
  • a suitable mobile phase is determined according to methods well known to those of ordinary skill in the art.
  • the mobile phase may include organic solvents such as alkanes, alcohols, ethers, chlorinated solvents as water, and buffered water.
  • Primary amines such as diethylamine (DEA), diisopropylamine, butyl amine, and triethylamine (TEA) may be used as bases.
  • acids include sulfuric acid, trifluoroacetic acid, hydrochloric acid, acetic acid, and formic acid.
  • Other inorganic mobile phase additives may also be used, such as KPF 6 , NaClO 4 , NaBF 4 , NaH 2 PO 4 .
  • the relative efficacies of compounds as inhibitors of an enzyme activity can be established by determining the concentrations at which each compound inhibits the activity to a predefined extent, then comparing the results.
  • the preferred determination is the concentration that inhibits 50% of the activity in a biochemical assay, i.e., the 50% inhibitory concentration or “IC50.”
  • IC50 determinations can be accomplished using conventional techniques known in the art. In general, an IC50 can be determined by measuring the activity of a given enzyme in the presence of a range of concentrations of the inhibitor under study. The experimentally obtained values of enzyme activity then are plotted against the inhibitor concentrations used.
  • the concentration of the inhibitor that shows 50% enzyme activity is taken as the IC50 value.
  • other inhibitory concentrations can be defined through appropriate determinations of activity. For example, in some settings it can be desirable to establish a 90% inhibitory concentration, i.e., IC90.
  • Treating refers to preventing a disorder from occurring in an animal that can be predisposed to the disorder, but has not yet been diagnosed as having it; inhibiting the disorder, e.g., slowing or arresting its development; relieving the disorder, e.g., causing its regression or elimination; or ameliorating the disorder, i.e., reducing the severity of symptoms associated with the disorder.
  • disorder is intended to encompass medical disorders, diseases, conditions, syndromes, and the like, without limitation.
  • the methods of the invention embrace various modes of treating an animal subject, preferably a mammal, more preferably a primate, and still more preferably a human.
  • mammalian animals that can be treated are, for example, humans, companion animals (pets), including dogs and cats; farm animals, including cattle, horses, sheep, pigs, and goats; laboratory animals, including rats, mice, rabbits, guinea pigs, and nonhuman primates; and zoo specimens.
  • Non-mammalian animals include, for example, birds, fish, reptiles, and amphibians. In general, any subject who would benefit from the compounds and compositions of the invention is appropriate for administration of the invention method.
  • compositions of the present invention can be manufactured using any conventional method, e.g., mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, melt-spinning, spray-drying, or lyophilizing processes.
  • An optimal pharmaceutical formulation can be determined by one of skill in the art depending on the route of administration and the desired dosage. Such formulations can influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the administered agent.
  • these pharmaceutical compositions can be formulated and administered systemically or locally.
  • compositions are formulated to contain suitable pharmaceutically acceptable carriers, and optionally can comprise excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
  • the administration modality will generally determine the nature of the carrier.
  • formulations for parenteral administration can comprise aqueous solutions of the active compounds in water-soluble form.
  • Carriers suitable for parenteral administration can be selected from among saline, buffered saline, dextrose, water, and other physiologically compatible solutions.
  • Preferred carriers for parenteral administration are physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiologically buffered saline.
  • penetrants appropriate to the particular barrier to be permeated are used in the formulation.
  • the formulation can include stabilizing materials, such as polyols (e.g., sucrose) and/or surfactants (e.g., nonionic surfactants), and the like.
  • stabilizing materials such as polyols (e.g., sucrose) and/or surfactants (e.g., nonionic surfactants), and the like.
  • formulations for parenteral use can comprise dispersions or suspensions of the active compounds prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, and synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran.
  • the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • Aqueous polymers that provide pH-sensitive solubilization and/or sustained release of the active agent also can be used as coatings or matrix structures, e.g., methacrylic polymers, such as the EUDRAGIT® series available from Röhm America Inc. (Piscataway, N.J.).
  • Emulsions e.g., oil-in-water and water-in-oil dispersions, also can be used, optionally stabilized by an emulsifying agent or dispersant (surface active materials; surfactants).
  • Suspensions can contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, gum tragacanth, and mixtures thereof.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, gum tragacanth, and mixtures thereof.
  • Liposomes containing the active agent also can be employed for parenteral administration.
  • Liposomes generally are derived from phospholipids or other lipid substances.
  • the compositions in liposome form also can contain other ingredients, such as stabilizers, preservatives, excipients, and the like.
  • Preferred lipids include phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods of forming liposomes are known in the art. See, e.g., Prescott (Ed.), Methods in Cell Biology , Vol. XIV, p. 33, Academic Press, New York (1976).
  • compositions comprising the agent in dosages suitable for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art.
  • Preparations formulated for oral administration can be in the form of tablets, pills, capsules, cachets, dragees, lozenges, liquids, gels, syrups, slurries, elixirs, suspensions, or powders.
  • pharmaceutical preparations for oral use can be obtained by combining the active compounds with a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores.
  • Oral formulations can employ liquid carriers similar in type to those described for parenteral use, e.g., buffered aqueous solutions, suspensions, and the like.
  • Preferred oral formulations include tablets, dragees, and gelatin capsules. These preparations can contain one or excipients, which include, without limitation:
  • Gelatin capsules include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol.
  • Push-fit capsules can contain the active ingredient(s) mixed with fillers, binders, lubricants, and/or stabilizers, etc.
  • the active compounds can be dissolved or suspended in suitable fluids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers.
  • Dragee cores can be provided with suitable coatings such as concentrated sugar solutions, which also can contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • suitable coatings such as concentrated sugar solutions, which also can contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • the pharmaceutical composition can be provided as a pharmaceutically acceptable salt of a compound of the invention. Salts are often more soluble in aqueous or other protonic solvents than the corresponding free acid or base forms. Pharmaceutically acceptable salts are well known in the art. Compounds that contain acidic moieties can form pharmaceutically acceptable salts with suitable cations. Suitable pharmaceutically acceptable cations include, for example, alkali metal (e.g., sodium or potassium) and alkaline earth (e.g., calcium or magnesium) cations.
  • alkali metal e.g., sodium or potassium
  • alkaline earth e.g., calcium or magnesium
  • compositions of the invention that contain basic moieties can form pharmaceutically acceptable acid addition salts with suitable acids.
  • suitable acids for example, Berge, et al., J Pharm Sci (1977) 66:1, describe pharmaceutically acceptable salts in detail.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable acid.
  • Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorolsulfonate, cinnamate, digluconate, formate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hippurate, hydroxyacetate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isothionate), lactate, maleate, malonate, mandelate, methanesulfonate or sulfate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, pyruvate, succinate
  • inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.
  • Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, or with ammonia or organic primary, secondary, or tertiary amine.
  • a suitable base such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, or with ammonia or organic primary, secondary, or tertiary amine.
  • Pharmaceutically acceptable basic addition salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like, and nontoxic quaternary ammonium and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, diethylammonium, triethylammonium, and the like.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.
  • Basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain alkyl halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; arylalkyl halides such as benzyl and phenethyl bromides; and others. Products having modified solubility or dispersibility are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates
  • Solvates for the purposes of the invention refer to those forms of the compounds of the invention which in solid or liquid state form a complex through coordination with solvent molecules.
  • Non-limiting examples of a solvent are water, acetone, methanol, ethanol and acetic acid.
  • the compounds of the invention may be prepared in the form of prodrugs, i.e., protected forms which release the compounds of the invention after administration to the subject.
  • the protecting groups are hydrolyzed in body fluids such as in the bloodstream thus releasing the active compound or are oxidized or reduced in vivo to release the active compound.
  • a discussion of prodrugs is found in Smith and Williams Introduction to the Principles of Drug Design, Smith, H.J.; Wright, 2nd ed., London (1988).
  • formulation and route of administration chosen will be tailored to the individual subject, the nature of the condition to be treated in the subject, and generally, the judgment of the attending practitioner.
  • the compounds of the invention are administered by injection most preferably by intravenous injection, but also by subcutaneous or intraperitoneal injection, and the like. Additional parenteral routes of administration include intramuscular and intraarticular injection.
  • the compounds are formulated in suitable liquid form with excipients as required.
  • the compositions may contain liposomes or other suitable carriers.
  • the solution is made isotonic using standard preparations such as Hank's solution.
  • the compounds may be formulated into tablets, capsules, syrups, powders, or other suitable forms for administration orally. By using suitable excipients, these compounds may also be administered through the mucosa using suppositories or intranasal sprays. Transdermal administration can also be effected by using suitable penetrants and controlling the rate of release.
  • the compounds may be administered as a single dose, a dose over time, as in i.v. or transdermal administration, or in multiple dosages. Dosages may be higher when the compounds are administered orally or transdermally as compared to, for example, i.v. administration.
  • Suitable dosage ranges for the compounds of the invention vary according to these considerations, but in general, the compounds are administered in the range of about 0.1 ⁇ g/kg-5 mg/kg of body weight; preferably the range is about 1 ⁇ g/kg-300 ⁇ g/kg of body weight; more preferably about 10 ⁇ g/kg-100 ⁇ g/kg of body weight.
  • the dosage range is from about 0.7 ⁇ g-350 mg; preferably about 700 ⁇ g-21 mg; most preferably about 700 ⁇ g-10 mg.
  • the compound is administered in the range of 5-15 mg/kg of body weight.
  • the compound is administered at a dose of less than 11 mg/kg of body weight.
  • the compound is administered at a dose of 10 mg/kg of body weight.
  • suitable dosage is an amount between 1-500 mg.
  • suitable dosage is an amount between 1-250 mg.
  • suitable dosage is an amount between 1-100 mg.
  • suitable dosage is an amount between 1-50 mg.
  • suitable dosage is an amount between 1-25 mg.
  • suitable dosage is an amount selected from the group consisting of 10 mg, 17 mg, 50 mg, 75 mg, 100 mg, 125 mg, 200 mg, 250 mg, and 400 mg, recognizing that small departures (+/ ⁇ 10%) are generally tolerated.
  • the suitable dosage is administered orally.
  • compositions comprising a compound of the invention formulated in a pharmaceutically acceptable carrier can be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • an article of manufacture such as a container comprising a dosage form of a compound of the invention and a label containing instructions for use of the compound.
  • Kits also are contemplated.
  • a kit can comprise a dosage form of a pharmaceutical composition and a package insert containing instructions for use of the composition in treatment of a medical condition.
  • conditions indicated on the label can include treatment of an inflammatory condition.
  • FIG. 1 The synthetic scheme for the preparation of 2-((6-amino-9H-purin-9-yl)methyl)-5-methyl-3-o-tolylquinazolin-4(3H)-one, 1, is shown in FIG. 1 .
  • 2-amino-6-methylbenzoic acid, 1′′ is reacted with 2-chloroacetyl chloride to produce the 2-( ⁇ 2-chloroacetamido)-6-methylbenzoic acid, 2′′.
  • Reaction with o-toluidine and phosphoryl trichloride yields the cyclized intermediate, 3′′.
  • the atropisomers of compound 1 may be resolved by high-pressure liquid chromatography (HPLC).
  • HPLC high-pressure liquid chromatography
  • Intermediate compounds 3′′ and 4′′ also contain atropisomers and resolution of either of these intermediates by HPLC can also be carried out prior to subsequent steps c and d, respectively.
  • the final conditions to separate the enantiomeric mixture of compound 1 include using CHIRALPAK®IATM column with dimensions of 250 mm L ⁇ 4.6 mm ID.
  • the sample was dissolved in ethanol and a mobile phase of 40:60:0.06 hexanes/isopropanol/diethylamine was used.
  • Flow conditions were at a rate of 1.0 mL/min, at 25° C. and UV detection of the product was monitored at 215 nm.
  • the run time was about 15 minutes.
  • the two main peaks at 7.4 min and 12.3 min represent the first and second atropisomers of compound 1, 1(S) and 1(R), respectively.
  • Reverse phase A sample of an enantiomeric mixture of 2-((6-amino-9H-purin-9-yl)methyl)-5-methyl-3-o-tolylquinazolin-4(3H)-one, 1, was combined in acetonitrile and used for screening. The sample was screened with CHIRALPAK® AD-RH®, AS-RH®, IBTM ICTM and CHIRALCEL®OJ-RH® columns, eluted with 30:70 pH 9 borate/acetonitrile and 30:70 100 mM aqueous KPF 6 /acetonitrile mobile phases.
  • the enantiomeric mixture is fully resolved in both the normal phase and reverse phase methods (Normal phase: CHIRALPAK® IA, 250 mm L ⁇ 4.6 mm ID, 40:60:0.06 hexanes/IPA/DEA, 1.0 mL/min, 25° C., 215 nm; Reverse phase: CHIRALCEL®OJ-RH, 150 mm L ⁇ 4.6 mm ID, 61:40 water/acetonitrile, 0.8 mL/min, 25° C.; 230 nm). It is observed that the two peaks resolved in the normal phase method elute in reverse order in the reverse phase method.
  • each isolated compound has been elucidated from x-ray crystallographic data.
  • the first peak to elute has been assigned the S configuration, shown as compound 1(S), and the second peak to elute has been assigned the R configuration, shown as compound 1(R).
  • This example demonstrates the in vitro activity of 1, 1(S) and 1(R) against p110alpha, p110beta, p110 gamma and p110delta isoforms.
  • This example follows the concentration of compound 1(S) and 1(R) in the blood plasma or rat, dog and human subjects over time.
  • Radiolabeled 1 In order to perform the pharmacokinetic studies, compound 1 was radiolabeled using 14 C at the ortho-methyl group of the phenyl at position 3 of the quinazolinone ring. Radiolabeled 1:
  • the tagged racemic mixture or separated atropisomers were administered in rats, dogs, and human subjects through oral and i.v. routes.
  • the compounds were dissolved in PEG 100 such that any difference in dissolution rates would not play a role in the pharmacokinetic profile of the compounds.
  • Modest solubility differences between compounds 1(S) and 1(R) were observed in a variety of aqueous solutions as summarized in FIG. 4 .
  • blood plasma of the subjects were sampled over time and evaluated by analytical HPLC methods developed to identify and measure concentrations of compound 1(S) or 1(R) present in the sample. It was observed that the most abundant isomer measured in the plasma is compound 1(S), which accounts for 70-80% of exposure to the subject.
  • FIG. 6 shows the blood plasma concentration of 1(S) and 1(R) over 24 hours after a single 50 mg/kg dose of racemic compound 1 was orally administered to female rats. 4 hours after dosing, the concentration of 1(S) steadily increases in the blood and 8 hours after dosing the average concentration of 1(R) is approximately one-fourth the concentration of 1(S). This demonstrates an in vivo difference in exposure between 1(S) and 1(R) when orally administered to rats, wherein the subject has increased exposure to 1(S) than 1(R).
  • FIG. 7 shows the blood plasma concentration of 1(S) and 1(R) over 24 hours after a single 50 mg/kg dose of racemic 1 was orally administered to female dogs.
  • the maximum concentration of compounds 1(S) and 1(R) is reached.
  • the concentration of 1(R) is less than half the concentration of compound 1(S).
  • FIG. 8 shows the blood plasma concentration of compounds 1(S) and 1(R) over 72 hours after a single 100 mg dose of racemic compound 1 was orally administered to human subjects.
  • the maximum concentration of compounds 1(S) and 1(R) is reached.
  • the concentration of compound 1(R) is less than half the concentration of compound 1(S), which accounts for approximately 70% of the exposure in the animal.
  • the concentrations of both compounds steadily decrease thereafter, at 72 hours post-dosing, the concentration of compound 1(S) is well over 10 times the concentration of compound 1(R).
  • This example compares oral versus intravenous administration of compounds 1(S) and 1(R) in rats.
  • a single dose of 1(S) or 1(R) (1.5 mg/kg) was administered either via a single bolus i.v. dose ( FIG. 9A ) or an oral dose ( FIG. 9B ) to female rat subjects.
  • the blood plasma concentration of either 1(S) or 1(R) was measured at different time points over a period of 24 hours after administration.
  • FIG. 9 shows the blood plasma concentration of 1(S) and 1(R) over a period of 24 hours after a single dose of 1(S) or 1(R) (1.5 mg/kg) administered either 1(S) a single bolus i.v. dose ( FIG. 9A ) or an oral dose ( FIG. 9B ) to female rat subjects.
  • the exposure level of 1(R) is approximately one-fifth the concentration of 1(S).
  • the concentration of both compounds is very low and within experimental error.
  • the concentration of 1(S) in blood plasma of rats that were orally administered the compounds was shown to greatly exceed the concentration of 1(R) at the 12 hour time point. This demonstrates an in vivo difference in exposure between 1(S) and 1(R) when either intravenously or orally administered to rats, wherein the subject has increased exposure to 1(S) relative to 1(R).
  • This example compares the pharmacokinetic parameters of compounds 1(S) and 1(R) in female Sprague Dawley (SD) rats following a single i.v. dose.
  • SD rats were administered a single bolus intravenous dose of 1(S) (1.5 mg/kg), 1(R) (1.5 mg/kg) or 1 (3 mg/kg) and the compound present in the subject was measured over time. Based on this data, pharmacokinetic parameters were calculated as summarized in Table 3.
  • Compound 1(R) has a volume of the terminal phase (Vz) value of 14,833 mL/kg, which is about 2.6 times greater than the Vz for either 1(S) or the racemic mixture.
  • This example compares pharmacokinetic parameters of compounds 1(S) and 1(R) in humans following a single oral dose of a racemic mixture.
  • Two dosing studies were performed. A single, 100 mg oral dose of racemic mixture 1 was orally administered to human subjects, and blood plasma concentration levels of each of the atropisomer compounds was measured over a period of 72 hours. In another study, a single, 10 mg oral dose of racemic mixture 1 was orally administered to human subjects, and blood plasma concentration levels of each of the atropisomer compounds was measured over a period of 120 hours.
  • FIGS. 10A and 10B show graphs of the blood plasma concentration of 1(S) and 1(R) plotted against a period of 72 hours after administration of a single, oral dose of 100 mg of the individual atropisomers.
  • the maximum concentration of 1(S) is over 2 times as great as the maximum concentration for 1(R).
  • the concentration of the compounds in the blood plasma decreases over the 72 hour period, the difference in concentration of the two compounds is maintained, if not further broadened. This difference in compound concentration in the blood appears to broaden because compound 1(S) decreases more gradually over time whereas compound 1(R) appears to be removed from the blood relatively more quickly.
  • the maximum blood plasma concentration of compound 1(S) is still about double the maximum concentration of compound 1(R), see FIGS. 10C and 10D .
  • This example compares the concentration of radiolabeled 1(S) and 1(R) in human plasma in the middle of a daily dosing regimen.
  • FIG. 11 depicts the concentration of 14 C radiolabeled compound 1(S) and 1(R) in total blood plasma.
  • FIG. 11 shows the pharmacokinetic profile for total radiolabeled material starting when the spiked material was administered on day 4, and continuing for several days thereafter.
  • Table 4 summarizes the half-life, C max and AUC values in human subjects for compounds 1(S) and 1(R) based on the data in FIG. 11 .
  • compound 1(S) has a half-life 6 times as long as the half-life of 1(R), which has a half-life of under 11 hours.
  • the C max value for 1(S) is twice as long as that of 1(R), and the AUC value for 1(S) is over 4 times as that of 1(R).
  • Compound 1(S) has a significantly longer half-life, as well as increased C max and AUC values; thus compound 1(S) produces greater exposure in humans compared to 1(R). Compound 1(S) therefore offers unexpected advantages over either 1(S) or a racemic mixture, and treatment of a human with 1(S) can provide a higher, more stable plasma level of active drug than treatment with 1(R) or the racemate, and simultaneously reduces exposure of the subject to other materials or metabolites of 1(R).
  • This example compares the formation of metabolic products in rats after administration of compounds 1(S) and 1(R).
  • a single 50 mg/kg oral dose of either atropisomer 1(S) or 1(R) was administered to rat subjects.
  • the rat urine was subsequently sampled and analyzed using LC-MS instrumentation.
  • FIGS. 12A and 12B show LC-MS results of the metabolites found in the urine. Rats which were exposed to 1(S) produced mainly one compound represented by a peak at 13.4 minutes and a second compound represented by a much smaller peak at 14.5 minutes, FIG. 12A .
  • the analytical traces of urine from rats which were administered compound 1(R) are characterized by three main peaks at 13.5, 14.4, and 15.6 minutes, and a small peak at minute 12.1, FIG. 12B .
  • This example compares the formation of metabolic products in human subjects after administration of compounds 1(S) and 1(R).
  • radiolabeled 1(S) or radiolabeled 1(R) was administered orally to a human subject.
  • Samples of plasma from the subject were tested 1 hour and 72 hours after administration, and were analyzed for their radiolabeled content.
  • the analysis used HPLC conditions that were known to separate 1(S) (eluting at about 21-22 minutes) from 1(R), so any interconversion between these species could be observed. It also resolves these two materials from the major metabolites formed from them in vivo.
  • FIGS. 13A-13D further illustrate the unexpected stability of 1(S) in vivo relative to 1(R).
  • the UV trace in each spectrum is provided as a retention time standard to confirm the identity of the peaks, but the important data to observe is the C-14 radiolabel signal, which is represented by small squares at the retention time for 1(S), 1(R), and the known metabolites of these compounds.
  • FIG. 13A there are two radiolabeled peaks observed, compound 1(S) (large peak at about 22 minutes) and a metabolite (small peak at about 14 minutes).
  • FIG. 13B there are two dominant C-14 data points, 1(R) at 22 minutes, and a metabolite at 14 minutes.
  • the metabolite level is nearly as large as the level of compound 1(R), even just one hour after administration of 1(R).
  • compound 1(S) results in less metabolite formation than compound 1(R) in human plasma, and remains largely unmodified after 1 hr.
  • the amount of metabolites formed from 1(S) is still less than the amount of the parent compound 1(S), FIG. 13C ; so most of the detected 14 C detected label corresponds to the active drug. It appears that a small amount of 1(R) is present at this point in time, suggesting that some interconversion of 1(S) to 1(R) may occur in vivo.
  • the abundance of metabolite after dosing with radiolabeled 1(R) suggests that compound 1(R) is metabolized by the human body relatively quickly.
  • the low to non-existent levels of metabolite in the plasma samples containing compound 1(S) suggests lower levels of metabolism, and the higher concentration of 1(S) 72 hours after administration shows this isomer provides longer exposure from a single dose.
  • This example compares the metabolic differences of the single 1(S) atropisomer over the racemic mixture.
  • the atropisomer 1(S) was shown to have a greater exposure than the racemic mixture, 1, in humans, which can be attributed to the greater metabolism of the atropisomer 1(R) and the greater metabolic stability of atropisomer 1(5).
  • plasma from human subjects dosed with the racemic mixture was confirmed to contain 2 metabolites and the 2 atropisomers.
  • One of the metabolites (Mlb) was greater than 10% of the parent levels of the active test article. The figure below indicates approximate relative abundance using the thickness of the arrow.
  • FIG. 14 shows a graph that compares the effect of vehicle, compound 1(S) or MTX on the severity of CIA in vivo. The graph plots the arthritis score as a function of the days post compound dosing and shows that compound 1(S) has activity in reducing the severity of arthritis in rat models.
  • FIG. 14 compares the effect of vehicle, compound 1(S), and varying levels of methotrexate on anti-collagen antibody levels in CIA rat models.
  • FIGS. 17A-D show images of tissue samples taken from CIA rats treated with vehicle, compound 1(S), or MTX (0.5 mg/kg and 2.5 mg/kg). The dark areas of the images is reduced in samples from subjects treated with compound 1(S) compared to the vehicle, and is similar to the images taken from subjects treated with MTX.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Diabetes (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Emergency Medicine (AREA)
  • Otolaryngology (AREA)
  • Transplantation (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US12/731,089 2009-03-24 2010-03-24 Atropisomers of 2-purinyl-3-tolyl-quinazolinone derivatives and methods of use Expired - Fee Related US8440677B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/731,089 US8440677B2 (en) 2009-03-24 2010-03-24 Atropisomers of 2-purinyl-3-tolyl-quinazolinone derivatives and methods of use

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US16298009P 2009-03-24 2009-03-24
US23155009P 2009-08-05 2009-08-05
US12/731,089 US8440677B2 (en) 2009-03-24 2010-03-24 Atropisomers of 2-purinyl-3-tolyl-quinazolinone derivatives and methods of use

Publications (2)

Publication Number Publication Date
US20100249155A1 US20100249155A1 (en) 2010-09-30
US8440677B2 true US8440677B2 (en) 2013-05-14

Family

ID=42289320

Family Applications (1)

Application Number Title Priority Date Filing Date
US12/731,089 Expired - Fee Related US8440677B2 (en) 2009-03-24 2010-03-24 Atropisomers of 2-purinyl-3-tolyl-quinazolinone derivatives and methods of use

Country Status (19)

Country Link
US (1) US8440677B2 (xx)
EP (1) EP2411391A1 (xx)
JP (1) JP2012521994A (xx)
KR (1) KR20120002995A (xx)
CN (1) CN102439012A (xx)
AP (1) AP2011005943A0 (xx)
AU (1) AU2010229968A1 (xx)
BR (1) BRPI1012333A2 (xx)
CA (1) CA2756347A1 (xx)
CL (1) CL2011002359A1 (xx)
CO (1) CO6450655A2 (xx)
EA (1) EA019499B1 (xx)
EC (1) ECSP11011412A (xx)
IL (1) IL215251A0 (xx)
MX (1) MX2011009955A (xx)
NZ (1) NZ595307A (xx)
PE (1) PE20120602A1 (xx)
SG (1) SG174529A1 (xx)
WO (1) WO2010111432A1 (xx)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9518046B2 (en) 2013-09-22 2016-12-13 Calitor Sciences, Llc Substituted aminopyrimidine compounds and methods of use
US10016425B2 (en) 2016-11-03 2018-07-10 King Saud University Anti-ulcerative colitis compound
US10836759B2 (en) 2016-06-22 2020-11-17 The University Of North Carolina At Chapel Hill Thiazole derivatives useful as mutant IDH1 inhibitors for treating cancer
WO2021207549A1 (en) 2020-04-10 2021-10-14 Gb005, Inc. Kinase inhibitors

Families Citing this family (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6667300B2 (en) 2000-04-25 2003-12-23 Icos Corporation Inhibitors of human phosphatidylinositol 3-kinase delta
WO2005016348A1 (en) * 2003-08-14 2005-02-24 Icos Corporation Method of inhibiting immune responses stimulated by an endogenous factor
LT2612862T (lt) 2004-05-13 2017-01-25 Icos Corporation Chinazolinonai kaip žmogaus fosfatidilinozitol-3-kinazės delta inhibitoriai
PT2355828T (pt) 2008-11-13 2018-07-02 Gilead Calistoga Llc Terapias para malignidades hematológicas
US9492449B2 (en) 2008-11-13 2016-11-15 Gilead Calistoga Llc Therapies for hematologic malignancies
EP2411391A1 (en) 2009-03-24 2012-02-01 Gilead Calistoga LLC Atropisomers of2-purinyl-3-tolyl-quinazolinone derivatives and methods of use
CA2759724A1 (en) * 2009-04-20 2010-10-28 Calistoga Pharmaceuticals, Inc. Methods of treatment for solid tumors
WO2010138577A1 (en) * 2009-05-29 2010-12-02 Merck Sharp & Dohme Corp. Radiolabeled pde10 inhibitors
US8691829B2 (en) * 2009-07-21 2014-04-08 Gilead Calistoga Llc Treatment of liver disorders with PI3K inhibitors
GB0918249D0 (en) 2009-10-19 2009-12-02 Respivert Ltd Compounds
UY33337A (es) 2010-10-18 2011-10-31 Respivert Ltd DERIVADOS SUSTITUIDOS DE 1H-PIRAZOL[ 3,4-d]PIRIMIDINA COMO INHIBIDORES DE LAS FOSFOINOSITIDA 3-QUINASAS
EP2518070A1 (en) * 2011-04-29 2012-10-31 Almirall, S.A. Pyrrolotriazinone derivatives as PI3K inhibitors
EP2518071A1 (en) * 2011-04-29 2012-10-31 Almirall, S.A. Imidazopyridine derivatives as PI3K inhibitors
AP3849A (en) 2011-12-15 2016-09-30 Novartis Ag Use of inhibitors of the activity or function of pi3k
AP2014007875A0 (en) 2012-03-05 2014-08-31 Gilead Calistoga Llc Polymorphic forms of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one
SI2834244T1 (sl) 2012-03-13 2016-12-30 Respivert Limited Inhibitorji kristalinične PI3 kinaze
CA2876995C (en) 2012-07-04 2020-10-06 Rhizen Pharmaceuticals Sa Novel selective pi3k delta inhibitors
WO2014015523A1 (en) * 2012-07-27 2014-01-30 Hutchison Medipharma Limited Novel heteroaryl and heterocycle compounds, compositions and methods
WO2014060431A1 (en) * 2012-10-16 2014-04-24 Almirall, S.A. Pyrrolotriazinone derivatives as pi3k inhibitors
GEP201706623B (en) * 2012-10-16 2017-02-10 Almirall Sa Pyrrolotriazinone derivatives as pi3k inhibitors
JP6434416B2 (ja) * 2012-11-08 2018-12-05 ライゼン・ファーマシューティカルズ・エスアー ＰＤＥ４阻害剤とＰＩ３δ阻害剤または二重ＰＩ３δ−γキナーゼ阻害剤とを含有する薬学的組成物
AR095353A1 (es) 2013-03-15 2015-10-07 Respivert Ltd Compuesto
JO3279B1 (ar) 2013-03-15 2018-09-16 Respivert Ltd مشتقات 2-((4- امينو -3- (3- فلورو-5- هيدروكسي فينيل)-h1- بيرازولو [d-3,4] بيرمدين-1-يل )ميثيل )- 3- (2- تراي فلورو ميثيل ) بينزيل ) كوينازولين -4 (h3)- واحد واستخدامها كمثبطات فوسفواينوسيتايد 3- كاينيز
UY35675A (es) 2013-07-24 2015-02-27 Novartis Ag Derivados sustituidos de quinazolin-4-ona
CN104447727B (zh) * 2013-09-02 2018-04-27 广东东阳光药业有限公司 取代的氨基嘧啶类化合物及其使用方法和用途
US9567337B2 (en) 2013-12-20 2017-02-14 Gilead Calistoga Llc Process methods for phosphatidylinositol 3-kinase inhibitors
US9708327B2 (en) 2013-12-20 2017-07-18 Gilead Calistoga Llc Polymorphic forms of a hydrochloride salt of (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one
SG11201607950SA (en) * 2014-05-27 2016-10-28 Almirall Sa Addition salts of (s)-2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-4-oxo-3-phenyl-3,4-dihydropyrrolo[1,2-f][1,2,4]triazine-5-carbonitrile
JP6987501B2 (ja) 2014-05-27 2022-01-05 ライゼン・ファーマシューティカルズ・エスアー 医薬製剤用ｐｉ３ｋデルタ選択的抑制剤の改良形態
MX2016016530A (es) 2014-06-13 2017-03-27 Gilead Sciences Inc Inhibidores de fosfatidilinositol 3-quinasa.
CR20160600A (es) 2014-07-04 2017-03-07 Lupin Ltd Quinolizione derivados como inhibidores pi3k
EP3334430A4 (en) 2015-08-13 2019-02-06 San Diego State University Foundation ATROPISOMERISM FOR INCREASED KINASE HEMMER ELECTIVITY
US11351209B2 (en) 2016-01-11 2022-06-07 Queen Mary University Of London Inhibitors of PI3K p-delta 110 for use in delivery of viruses in the treatment of cancer
CN112601746B (zh) * 2018-08-21 2022-09-16 南京明德新药研发有限公司 吡唑并嘧啶衍生物及其作为pi3k抑制剂的应用

Citations (98)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3322756A (en) 1963-05-18 1967-05-30 Hoechst Ag 2-aminoalkyl-3-hydrocarbon quinazolones-(4)
US3691016A (en) 1970-04-17 1972-09-12 Monsanto Co Process for the preparation of insoluble enzymes
GB1356763A (en) 1971-04-21 1974-06-12 Merck & Co Inc Substituted benzimidazole derivatives
US3897432A (en) 1971-04-21 1975-07-29 Merck & Co Inc Substituted benzimidazole derivatives
US3969287A (en) 1972-12-08 1976-07-13 Boehringer Mannheim Gmbh Carrier-bound protein prepared by reacting the protein with an acylating or alkylating compound having a carrier-bonding group and reacting the product with a carrier
US3984555A (en) 1970-06-05 1976-10-05 Byk Gulden Lomberg Chemische Fabrik Gesellschaft Mit Beschrankter Haftung Therapeutic piperazinylalkyl-quinazolone-(4)-derivatives
GB2017097A (en) 1978-03-22 1979-10-03 Bayer Ag Quinazoline derivatives
US4179337A (en) 1973-07-20 1979-12-18 Davis Frank F Non-immunogenic polypeptides
US4183931A (en) 1977-09-08 1980-01-15 Research Corporation 2-Ketoalkyl-4(3H)-quinazolinones
US4195128A (en) 1976-05-03 1980-03-25 Bayer Aktiengesellschaft Polymeric carrier bound ligands
JPS55118917A (en) 1979-03-06 1980-09-12 Mitsubishi Electric Corp Production of quinazolone ring-containing epoxy resin
JPS55118918A (en) 1979-03-06 1980-09-12 Mitsubishi Electric Corp Production of quinazolone ring-containing epoxy resin
US4225489A (en) 1976-09-30 1980-09-30 Bayer Aktiengesellschaft Heterocyclic azo dyes and pigments containing 4-quinazolinone moieties
US4229537A (en) 1978-02-09 1980-10-21 New York University Preparation of trichloro-s-triazine activated supports for coupling ligands
JPS562322A (en) 1979-06-20 1981-01-12 Mitsubishi Electric Corp Preparation of polyamide resin
US4247642A (en) 1977-02-17 1981-01-27 Sumitomo Chemical Company, Limited Enzyme immobilization with pullulan gel
US4289872A (en) 1979-04-06 1981-09-15 Allied Corporation Macromolecular highly branched homogeneous compound based on lysine units
US4301144A (en) 1979-07-11 1981-11-17 Ajinomoto Company, Incorporated Blood substitute containing modified hemoglobin
US4330440A (en) 1977-02-08 1982-05-18 Development Finance Corporation Of New Zealand Activated matrix and method of activation
US4496689A (en) 1983-12-27 1985-01-29 Miles Laboratories, Inc. Covalently attached complex of alpha-1-proteinase inhibitor with a water soluble polymer
US4640835A (en) 1981-10-30 1987-02-03 Nippon Chemiphar Company, Ltd. Plasminogen activator derivatives
US4670417A (en) 1985-06-19 1987-06-02 Ajinomoto Co., Inc. Hemoglobin combined with a poly(alkylene oxide)
US4791192A (en) 1986-06-26 1988-12-13 Takeda Chemical Industries, Ltd. Chemically modified protein with polyethyleneglycol
EP0364598A1 (en) 1988-03-02 1990-04-25 Yoshitomi Pharmaceutical Industries, Ltd. 3,4-dihydrothieno ¬2,3-d pyrimidine compounds and pharmaceutical application thereof
US4925673A (en) 1986-08-18 1990-05-15 Clinical Technologies Associates, Inc. Delivery systems for pharmacological agents encapsulated with proteinoids
US5013556A (en) 1989-10-20 1991-05-07 Liposome Technology, Inc. Liposomes with enhanced circulation time
EP0525960A1 (en) 1991-06-18 1993-02-03 American Home Products Corporation Use of rapamycin for the treatment of adult T-cell leukemia/lymphoma
US5225347A (en) 1989-09-25 1993-07-06 Innovir Laboratories, Inc. Therapeutic ribozyme compositions and expression vectors
US5229490A (en) 1987-05-06 1993-07-20 The Rockefeller University Multiple antigen peptide system
WO1993021259A1 (en) 1992-04-14 1993-10-28 Cornell Research Foundation Inc. Dendritic based macromolecules and method of production
WO1994017090A1 (en) 1993-01-20 1994-08-04 Glaxo Group Limited 2,6-diaminopurine derivatives
US5378725A (en) 1993-07-19 1995-01-03 The Arizona Board Of Regents Inhibition of phosphatidylinositol 3-kinase with wortmannin and analogs thereof
WO1995024379A1 (en) 1994-03-09 1995-09-14 Newcastle University Ventures Limited Benzamide analogs, useful as parp (adp-ribosyltransferase, adprt) dna repair enzyme inhibitors
EP0675124A2 (en) 1994-03-28 1995-10-04 Japan Energy Corporation Purine derivatives and suppressants for inflammatory diseases
US5480906A (en) 1994-07-01 1996-01-02 Eli Lilly And Company Stereochemical Wortmannin derivatives
WO1996004923A1 (en) 1994-08-12 1996-02-22 Pro-Neuron, Inc. Methods for treating sepsis or inflammatory diseases with oxypurine nucleosides
EP0716857A1 (en) 1994-12-13 1996-06-19 American Home Products Corporation Use of rapamycin for treating anemia
WO1996025488A1 (en) 1995-02-17 1996-08-22 The Regents Of The University Of California A constitutively active phosphatidylinositol 3-kinase and uses thereof
WO1996032478A1 (en) 1995-04-14 1996-10-17 Genentech, Inc. Altered polypeptides with increased half-life
WO1997034631A1 (en) 1996-03-18 1997-09-25 Board Of Regents, The University Of Texas System Immunoglobin-like domains with increased half lives
WO1997041097A2 (en) 1996-12-31 1997-11-06 Dr. Reddy's Research Foundation Novel heterocyclic compounds process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
WO1997043276A1 (en) 1996-05-15 1997-11-20 Pfizer Inc. Novel 2,3 disubstituted-4(3h)-quinazolinones
WO1997046688A1 (en) 1996-06-01 1997-12-11 Ludwig Institute For Cancer Research Lipid kinase
USRE35862E (en) 1986-08-18 1998-07-28 Emisphere Technologies, Inc. Delivery systems for pharmacological agents encapsulated with proteinoids
WO1998033802A1 (en) 1997-02-01 1998-08-06 Newcastle University Ventures Limited Quinazolinone compounds
WO1998038173A1 (en) 1997-02-28 1998-09-03 Pfizer Products Inc. Atropisomers of 3-aryl-4(3h)-quinazolinones and their use as ampa-receptor antagonists
EP0884310A1 (en) 1997-06-09 1998-12-16 Pfizer Products Inc. Quinazolin-4-one ampa antagonists
US5858753A (en) 1996-11-25 1999-01-12 Icos Corporation Lipid kinase
WO1999008501A2 (en) 1998-04-23 1999-02-25 Dr. Reddy's Research Foundation New heterocyclic compounds and their use in medicine, process for their preparation and pharmaceutical compositions containing them
EP0900568A2 (en) 1997-09-05 1999-03-10 Pfizer Products Inc. AMPA antagonists for the treatment of dyskinesias associated with dopamine agonist therapy
WO1999034804A1 (en) 1998-01-08 1999-07-15 The University Of Virginia Patent Foundation A2a adenosine receptor agonists
US5948664A (en) 1996-02-29 1999-09-07 The Regents Of The University Of California PI 3-kinase polypeptides
US6046049A (en) 1999-07-19 2000-04-04 Isis Pharmaceuticals Inc. Antisense modulation of PI3 kinase p110 delta expression
US6048970A (en) 1998-05-22 2000-04-11 Incyte Pharmaceuticals, Inc. Prostate growth-associated membrane proteins
EP0716875B1 (en) 1994-12-15 2000-12-27 The Kansai Electric Power Co., Inc. Process for removing carbon dioxide and nitrogen oxides from combustion gases
WO2001000881A1 (en) 1999-06-25 2001-01-04 Isis Pharmaceuticals, Inc. Antisense modulation of pi3k p85 expression
US6277981B1 (en) 1997-07-03 2001-08-21 Thomas Jefferson University Method for design and selection of efficacious antisense oligonucleotides
US6369038B1 (en) 1991-04-25 2002-04-09 Genset Closed antisense and sense oligonucleotides and their applications
US6380204B1 (en) 1997-02-28 2002-04-30 Pfizer Inc Atropisomers of 3-heteroaryl-4(3H)-quinazolinones for the treatment of neurodegenerative and CNS-trauma related conditions
US6410224B1 (en) 1992-12-07 2002-06-25 Ribozyme Pharmaceuticals, Inc. Ribozyme treatment of diseases or conditions related to levels of NF-κB
US6518277B1 (en) 2000-04-25 2003-02-11 Icos Corporation Inhibitors of human phosphatidylinositol 3-kinase delta
US6667300B2 (en) 2000-04-25 2003-12-23 Icos Corporation Inhibitors of human phosphatidylinositol 3-kinase delta
WO2004007491A1 (en) 2002-07-10 2004-01-22 Applied Research Systems Ars Holding N.V. Azolidinone-vinyl fused-benzene derivatives
US20040023390A1 (en) 2002-08-05 2004-02-05 Davidson Beverly L. SiRNA-mediated gene silencing with viral vectors
WO2004012768A1 (en) 2002-07-31 2004-02-12 Novartis Ag Tolerance induction with help of a combination of a lfa-1 inhibitor and a costimulation inhibitor and/or a mtor inhibitor
US6696250B1 (en) 1986-12-03 2004-02-24 Competitive Technologies, Inc. RNA ribozyme polymerases, dephosphorylases, restriction endoribonucleases and methods
WO2004026285A2 (en) 2002-09-19 2004-04-01 Amgen Canada Inc. Compositions and methods for treating heart disease
WO2004029055A1 (en) 2002-09-30 2004-04-08 Bayer Pharmaceuticals Corporation Fused azole-pyrimidine derivatives
US20040092561A1 (en) 2002-11-07 2004-05-13 Thomas Ruckle Azolidinone-vinyl fused -benzene derivatives
US20040121996A1 (en) 2002-12-06 2004-06-24 Nicole Barvian Benzoxazin-3-ones and derivatives thereof as therapeutic agents
WO2004056820A1 (en) 2002-12-20 2004-07-08 Warner-Lambert Company Llc Benzoxazines and derivatives thereof as inhibitors of pi3ks
WO2004089925A1 (en) 2003-04-03 2004-10-21 Semafore Pharmaceuticals, Inc. Pi-3 kinase inhibitor prodrugs
US20040248953A1 (en) 2003-06-05 2004-12-09 Gogliotti Rocco Dean 3-Arylsulfanyl and 3-heteroarylsulfanyl substituted benzo[b]thiophenes as therapeutic agents
US20040248954A1 (en) 2003-06-05 2004-12-09 Gogliotti Rocco Dean Cycloalkylsulfanyl substituted benzo[b]thiophenes as therapeutic agents
WO2004108713A1 (en) 2003-06-05 2004-12-16 Warner-Lambert Company Llc Cycloalkyl and heterocycloalkyl substituted benzothiophenes as therapeutic agents
WO2004108709A1 (en) 2003-06-05 2004-12-16 Warner-Lambert Company Llc Tetrazol benzofurancarboxamides with p13k aktivity as therapeutic agents
WO2004108708A1 (en) 2003-06-05 2004-12-16 Warner-Lambert Company Llc 3-substituted indoles and derivatives thereof as therapeutic agents
WO2004108715A1 (en) 2003-06-05 2004-12-16 Warner-Lambert Company Llc 3-aryloxy and 3-heteroaryloxy substituted benzo(b) thiophenes as therapeutic agents with pi3k activity
WO2005016348A1 (en) 2003-08-14 2005-02-24 Icos Corporation Method of inhibiting immune responses stimulated by an endogenous factor
WO2005016349A1 (en) 2003-08-14 2005-02-24 Icos Corporation Methods of inhibiting leukocyte accumulation
US20050239809A1 (en) * 2004-01-08 2005-10-27 Watts Stephanie W Methods for treating and preventing hypertension and hypertension-related disorders
WO2005113556A1 (en) 2004-05-13 2005-12-01 Icos Corporation Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta
WO2005117889A1 (en) 2004-05-25 2005-12-15 Icos Corporation Methods for treating and/or preventing aberrant proliferation of hematopoietic
WO2005120511A1 (en) 2004-06-04 2005-12-22 Icos Corporation Methods for treating mast cell disorders
US20060079538A1 (en) 2004-05-13 2006-04-13 Dennis Hallahan Methods for inhibiting angiogenesis
WO2006089106A2 (en) 2005-02-17 2006-08-24 Icos Corporation Phosphoinositide 3-kinase inhibitors for inhibiting leukocyte accumulation
WO2007076085A2 (en) 2005-12-22 2007-07-05 Prolexys Pharmaceuticals, Inc . Fused pyrimidones and thiopyrimidones, and uses thereof
WO2008064018A1 (en) 2006-11-13 2008-05-29 Eli Lilly & Co. Thienopyrimidinones for treatment of inflammatory disorders and cancers
EP1939203A2 (en) 2000-04-25 2008-07-02 ICOS Corporation Inhibitors of human phosphatidyl-inositol 3-kinase delta isoform
WO2009046448A1 (en) 2007-10-04 2009-04-09 Intellikine, Inc. Chemical entities and therapeutic uses thereof
WO2009058361A1 (en) 2007-10-31 2009-05-07 Dynavax Technologies Corp. Inhibition of type i ifn production
WO2009088986A1 (en) 2008-01-04 2009-07-16 Intellikine, Inc. Certain chemical entities, compositions and methods
WO2010057048A1 (en) 2008-11-13 2010-05-20 Calistoga Pharmaceuticals Inc. Therapies for hematologic malignancies
WO2010065923A2 (en) 2008-12-04 2010-06-10 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Phosphatidylinositol-3-kinase p110 delta-targeted drugs in the treatment of cns disorders
US20100249155A1 (en) 2009-03-24 2010-09-30 Evarts Jerry B Atropisomers of 2-purinyl-3-tolyl-quinazolinone derivatives and methods of use
WO2010123931A1 (en) 2009-04-20 2010-10-28 Calistoga Pharmaceuticals Inc. Methods of treatment for solid tumors
WO2011011550A1 (en) * 2009-07-21 2011-01-27 Calistoga Pharmaceuticals Inc. Treatment of liver disorders with pi3k inhibitors
WO2011153514A2 (en) 2010-06-03 2011-12-08 Pharmacyclics, Inc. The use of inhibitors of bruton's tyrosine kinase (btk)

Patent Citations (136)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3322756A (en) 1963-05-18 1967-05-30 Hoechst Ag 2-aminoalkyl-3-hydrocarbon quinazolones-(4)
US3691016A (en) 1970-04-17 1972-09-12 Monsanto Co Process for the preparation of insoluble enzymes
US3984555A (en) 1970-06-05 1976-10-05 Byk Gulden Lomberg Chemische Fabrik Gesellschaft Mit Beschrankter Haftung Therapeutic piperazinylalkyl-quinazolone-(4)-derivatives
GB1356763A (en) 1971-04-21 1974-06-12 Merck & Co Inc Substituted benzimidazole derivatives
US3897432A (en) 1971-04-21 1975-07-29 Merck & Co Inc Substituted benzimidazole derivatives
US3969287A (en) 1972-12-08 1976-07-13 Boehringer Mannheim Gmbh Carrier-bound protein prepared by reacting the protein with an acylating or alkylating compound having a carrier-bonding group and reacting the product with a carrier
US4179337A (en) 1973-07-20 1979-12-18 Davis Frank F Non-immunogenic polypeptides
US4195128A (en) 1976-05-03 1980-03-25 Bayer Aktiengesellschaft Polymeric carrier bound ligands
US4225489A (en) 1976-09-30 1980-09-30 Bayer Aktiengesellschaft Heterocyclic azo dyes and pigments containing 4-quinazolinone moieties
US4330440A (en) 1977-02-08 1982-05-18 Development Finance Corporation Of New Zealand Activated matrix and method of activation
US4247642A (en) 1977-02-17 1981-01-27 Sumitomo Chemical Company, Limited Enzyme immobilization with pullulan gel
US4183931A (en) 1977-09-08 1980-01-15 Research Corporation 2-Ketoalkyl-4(3H)-quinazolinones
US4229537A (en) 1978-02-09 1980-10-21 New York University Preparation of trichloro-s-triazine activated supports for coupling ligands
GB2017097A (en) 1978-03-22 1979-10-03 Bayer Ag Quinazoline derivatives
JPS55118917A (en) 1979-03-06 1980-09-12 Mitsubishi Electric Corp Production of quinazolone ring-containing epoxy resin
JPS55118918A (en) 1979-03-06 1980-09-12 Mitsubishi Electric Corp Production of quinazolone ring-containing epoxy resin
US4289872A (en) 1979-04-06 1981-09-15 Allied Corporation Macromolecular highly branched homogeneous compound based on lysine units
JPS562322A (en) 1979-06-20 1981-01-12 Mitsubishi Electric Corp Preparation of polyamide resin
US4301144A (en) 1979-07-11 1981-11-17 Ajinomoto Company, Incorporated Blood substitute containing modified hemoglobin
US4640835A (en) 1981-10-30 1987-02-03 Nippon Chemiphar Company, Ltd. Plasminogen activator derivatives
US4496689A (en) 1983-12-27 1985-01-29 Miles Laboratories, Inc. Covalently attached complex of alpha-1-proteinase inhibitor with a water soluble polymer
US4670417A (en) 1985-06-19 1987-06-02 Ajinomoto Co., Inc. Hemoglobin combined with a poly(alkylene oxide)
US4791192A (en) 1986-06-26 1988-12-13 Takeda Chemical Industries, Ltd. Chemically modified protein with polyethyleneglycol
US4925673A (en) 1986-08-18 1990-05-15 Clinical Technologies Associates, Inc. Delivery systems for pharmacological agents encapsulated with proteinoids
USRE35862E (en) 1986-08-18 1998-07-28 Emisphere Technologies, Inc. Delivery systems for pharmacological agents encapsulated with proteinoids
US6696250B1 (en) 1986-12-03 2004-02-24 Competitive Technologies, Inc. RNA ribozyme polymerases, dephosphorylases, restriction endoribonucleases and methods
US5229490A (en) 1987-05-06 1993-07-20 The Rockefeller University Multiple antigen peptide system
EP0364598A1 (en) 1988-03-02 1990-04-25 Yoshitomi Pharmaceutical Industries, Ltd. 3,4-dihydrothieno ¬2,3-d pyrimidine compounds and pharmaceutical application thereof
US5225347A (en) 1989-09-25 1993-07-06 Innovir Laboratories, Inc. Therapeutic ribozyme compositions and expression vectors
US5013556A (en) 1989-10-20 1991-05-07 Liposome Technology, Inc. Liposomes with enhanced circulation time
US6369038B1 (en) 1991-04-25 2002-04-09 Genset Closed antisense and sense oligonucleotides and their applications
EP0525960A1 (en) 1991-06-18 1993-02-03 American Home Products Corporation Use of rapamycin for the treatment of adult T-cell leukemia/lymphoma
EP0525960B1 (en) 1991-06-18 1996-03-20 American Home Products Corporation Use of rapamycin for the treatment of adult T-cell leukemia/lymphoma
WO1993021259A1 (en) 1992-04-14 1993-10-28 Cornell Research Foundation Inc. Dendritic based macromolecules and method of production
US6410224B1 (en) 1992-12-07 2002-06-25 Ribozyme Pharmaceuticals, Inc. Ribozyme treatment of diseases or conditions related to levels of NF-κB
WO1994017090A1 (en) 1993-01-20 1994-08-04 Glaxo Group Limited 2,6-diaminopurine derivatives
US5378725A (en) 1993-07-19 1995-01-03 The Arizona Board Of Regents Inhibition of phosphatidylinositol 3-kinase with wortmannin and analogs thereof
WO1995024379A1 (en) 1994-03-09 1995-09-14 Newcastle University Ventures Limited Benzamide analogs, useful as parp (adp-ribosyltransferase, adprt) dna repair enzyme inhibitors
EP0675124A2 (en) 1994-03-28 1995-10-04 Japan Energy Corporation Purine derivatives and suppressants for inflammatory diseases
US5480906A (en) 1994-07-01 1996-01-02 Eli Lilly And Company Stereochemical Wortmannin derivatives
WO1996004923A1 (en) 1994-08-12 1996-02-22 Pro-Neuron, Inc. Methods for treating sepsis or inflammatory diseases with oxypurine nucleosides
EP0716857A1 (en) 1994-12-13 1996-06-19 American Home Products Corporation Use of rapamycin for treating anemia
EP0716875B1 (en) 1994-12-15 2000-12-27 The Kansai Electric Power Co., Inc. Process for removing carbon dioxide and nitrogen oxides from combustion gases
WO1996025488A1 (en) 1995-02-17 1996-08-22 The Regents Of The University Of California A constitutively active phosphatidylinositol 3-kinase and uses thereof
WO1996032478A1 (en) 1995-04-14 1996-10-17 Genentech, Inc. Altered polypeptides with increased half-life
US5948664A (en) 1996-02-29 1999-09-07 The Regents Of The University Of California PI 3-kinase polypeptides
US6291220B1 (en) 1996-02-29 2001-09-18 The Regents Of The University Of California Polynucleotides encoding phosphatidylinositol 3-kinases
WO1997034631A1 (en) 1996-03-18 1997-09-25 Board Of Regents, The University Of Texas System Immunoglobin-like domains with increased half lives
WO1997043276A1 (en) 1996-05-15 1997-11-20 Pfizer Inc. Novel 2,3 disubstituted-4(3h)-quinazolinones
US6482623B1 (en) 1996-06-01 2002-11-19 Ludwig Institute For Cancer Research Lipid kinase
WO1997046688A1 (en) 1996-06-01 1997-12-11 Ludwig Institute For Cancer Research Lipid kinase
US5882910A (en) 1996-11-25 1999-03-16 Icos Corporation Lipid kinase
US5985589A (en) 1996-11-25 1999-11-16 Icos Corporation Lipid kinase
US5858753A (en) 1996-11-25 1999-01-12 Icos Corporation Lipid kinase
WO1997041097A2 (en) 1996-12-31 1997-11-06 Dr. Reddy's Research Foundation Novel heterocyclic compounds process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
WO1998033802A1 (en) 1997-02-01 1998-08-06 Newcastle University Ventures Limited Quinazolinone compounds
US6380204B1 (en) 1997-02-28 2002-04-30 Pfizer Inc Atropisomers of 3-heteroaryl-4(3H)-quinazolinones for the treatment of neurodegenerative and CNS-trauma related conditions
WO1998038173A1 (en) 1997-02-28 1998-09-03 Pfizer Products Inc. Atropisomers of 3-aryl-4(3h)-quinazolinones and their use as ampa-receptor antagonists
EP0884310B1 (en) 1997-06-09 2005-09-07 Pfizer Products Inc. Quinazolin-4-one ampa antagonists
EP0884310A1 (en) 1997-06-09 1998-12-16 Pfizer Products Inc. Quinazolin-4-one ampa antagonists
US6277981B1 (en) 1997-07-03 2001-08-21 Thomas Jefferson University Method for design and selection of efficacious antisense oligonucleotides
EP0900568A2 (en) 1997-09-05 1999-03-10 Pfizer Products Inc. AMPA antagonists for the treatment of dyskinesias associated with dopamine agonist therapy
WO1999034804A1 (en) 1998-01-08 1999-07-15 The University Of Virginia Patent Foundation A2a adenosine receptor agonists
WO1999008501A2 (en) 1998-04-23 1999-02-25 Dr. Reddy's Research Foundation New heterocyclic compounds and their use in medicine, process for their preparation and pharmaceutical compositions containing them
US6048970A (en) 1998-05-22 2000-04-11 Incyte Pharmaceuticals, Inc. Prostate growth-associated membrane proteins
WO2001000881A1 (en) 1999-06-25 2001-01-04 Isis Pharmaceuticals, Inc. Antisense modulation of pi3k p85 expression
US6046049A (en) 1999-07-19 2000-04-04 Isis Pharmaceuticals Inc. Antisense modulation of PI3 kinase p110 delta expression
US6667300B2 (en) 2000-04-25 2003-12-23 Icos Corporation Inhibitors of human phosphatidylinositol 3-kinase delta
US20120172591A1 (en) * 2000-04-25 2012-07-05 Icos Corporation Inhibitors of human phosphatidylinositol 3-kinase delta
US6800620B2 (en) 2000-04-25 2004-10-05 Icos Inhibitors of human phosphatidylinositol 3-kinase delta
US8138195B2 (en) 2000-04-25 2012-03-20 Icos Corporation Inhibitors of human phosphatidylinositol 3-kinase delta
US20100168139A1 (en) 2000-04-25 2010-07-01 Chanchal Sadhu Inhibitors of human phosphatidylinositol 3-kinase delta
US20100152211A1 (en) 2000-04-25 2010-06-17 Chanchal Sadhu Inhibitors of human phosphatidylinositol 3-kinase delta
EP1939203A2 (en) 2000-04-25 2008-07-02 ICOS Corporation Inhibitors of human phosphatidyl-inositol 3-kinase delta isoform
US20050261317A1 (en) 2000-04-25 2005-11-24 Icos Corporation Inhibitors of human phosphatidylinositol 3-kinase delta
US6949535B2 (en) 2000-04-25 2005-09-27 Icos Corporation Inhibitors of human phosphatidyl-inositol 3-kinase delta
US6518277B1 (en) 2000-04-25 2003-02-11 Icos Corporation Inhibitors of human phosphatidylinositol 3-kinase delta
WO2004007491A1 (en) 2002-07-10 2004-01-22 Applied Research Systems Ars Holding N.V. Azolidinone-vinyl fused-benzene derivatives
WO2004012768A1 (en) 2002-07-31 2004-02-12 Novartis Ag Tolerance induction with help of a combination of a lfa-1 inhibitor and a costimulation inhibitor and/or a mtor inhibitor
US20040023390A1 (en) 2002-08-05 2004-02-05 Davidson Beverly L. SiRNA-mediated gene silencing with viral vectors
WO2004026285A2 (en) 2002-09-19 2004-04-01 Amgen Canada Inc. Compositions and methods for treating heart disease
WO2004026285A3 (en) 2002-09-19 2004-07-29 Univ Health Network Compositions and methods for treating heart disease
WO2004029055A1 (en) 2002-09-30 2004-04-08 Bayer Pharmaceuticals Corporation Fused azole-pyrimidine derivatives
US20040092561A1 (en) 2002-11-07 2004-05-13 Thomas Ruckle Azolidinone-vinyl fused -benzene derivatives
WO2004052373A1 (en) 2002-12-06 2004-06-24 Warner-Lambert Company Llc Benzoxazin-3-ones and derivatives thereof as inhibitors of pi3k
US20040121996A1 (en) 2002-12-06 2004-06-24 Nicole Barvian Benzoxazin-3-ones and derivatives thereof as therapeutic agents
WO2004056820A1 (en) 2002-12-20 2004-07-08 Warner-Lambert Company Llc Benzoxazines and derivatives thereof as inhibitors of pi3ks
US20040138199A1 (en) 2002-12-20 2004-07-15 Gogliotti Rocco Dean Benzoxazines and derivatives thereof as therapeutic agents
WO2004089925A1 (en) 2003-04-03 2004-10-21 Semafore Pharmaceuticals, Inc. Pi-3 kinase inhibitor prodrugs
US20040242631A1 (en) 2003-04-03 2004-12-02 Garlich Joseph R. PI-3 kinase inhibitor prodrugs
WO2004108713A1 (en) 2003-06-05 2004-12-16 Warner-Lambert Company Llc Cycloalkyl and heterocycloalkyl substituted benzothiophenes as therapeutic agents
US20050020631A1 (en) 2003-06-05 2005-01-27 Gogliotti Rocco Dean 3-Substituted benzofurans as therapeutic agents
US20050020630A1 (en) 2003-06-05 2005-01-27 Michael Connolly Cycloalkyl and heterocycloalkyl substituted benzothiophenes as therapeutic agents
US20050004195A1 (en) 2003-06-05 2005-01-06 Para Kimberly Suzanne 3-Substituted indoles and derivatives thereof as therapeutic agents
US20040259926A1 (en) 2003-06-05 2004-12-23 Bruendl Michelle M. 3-Aryloxy and 3-heteroaryloxy substituted benzo[b]thiophenes as therapeutic agents
WO2004108715A1 (en) 2003-06-05 2004-12-16 Warner-Lambert Company Llc 3-aryloxy and 3-heteroaryloxy substituted benzo(b) thiophenes as therapeutic agents with pi3k activity
WO2004108708A1 (en) 2003-06-05 2004-12-16 Warner-Lambert Company Llc 3-substituted indoles and derivatives thereof as therapeutic agents
WO2004108709A1 (en) 2003-06-05 2004-12-16 Warner-Lambert Company Llc Tetrazol benzofurancarboxamides with p13k aktivity as therapeutic agents
US20040248954A1 (en) 2003-06-05 2004-12-09 Gogliotti Rocco Dean Cycloalkylsulfanyl substituted benzo[b]thiophenes as therapeutic agents
US20040248953A1 (en) 2003-06-05 2004-12-09 Gogliotti Rocco Dean 3-Arylsulfanyl and 3-heteroarylsulfanyl substituted benzo[b]thiophenes as therapeutic agents
WO2005016349A1 (en) 2003-08-14 2005-02-24 Icos Corporation Methods of inhibiting leukocyte accumulation
US20050054614A1 (en) 2003-08-14 2005-03-10 Diacovo Thomas G. Methods of inhibiting leukocyte accumulation
WO2005016348A1 (en) 2003-08-14 2005-02-24 Icos Corporation Method of inhibiting immune responses stimulated by an endogenous factor
US20100029693A1 (en) 2003-08-14 2010-02-04 Jason Douangpanya Novel pi3k delta inhibitors and methods of use thereof
US20050043239A1 (en) 2003-08-14 2005-02-24 Jason Douangpanya Methods of inhibiting immune responses stimulated by an endogenous factor
WO2005067901A3 (en) 2004-01-08 2005-12-01 Univ Michigan State Methods for treating and preventing hypertension and hypertension-related disorders
US20050239809A1 (en) * 2004-01-08 2005-10-27 Watts Stephanie W Methods for treating and preventing hypertension and hypertension-related disorders
US20120015964A1 (en) * 2004-05-13 2012-01-19 Icos Corporation Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta
US7932260B2 (en) 2004-05-13 2011-04-26 Icos Corporation Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta
US20100256167A1 (en) 2004-05-13 2010-10-07 Fowler Kerry W Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta
US20100256168A1 (en) 2004-05-13 2010-10-07 Fowler Kerry W Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta
WO2005113556A1 (en) 2004-05-13 2005-12-01 Icos Corporation Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta
US20080275067A1 (en) 2004-05-13 2008-11-06 Icos Corporation Quinazolinones as Inhibitors of Human Phosphatidylinositol 3-Kinase Delta
US20060079538A1 (en) 2004-05-13 2006-04-13 Dennis Hallahan Methods for inhibiting angiogenesis
US20060106038A1 (en) 2004-05-25 2006-05-18 Icos Corporation Methods for treating and/or preventing aberrant proliferation of hematopoietic cells
WO2005117889A1 (en) 2004-05-25 2005-12-15 Icos Corporation Methods for treating and/or preventing aberrant proliferation of hematopoietic
WO2005120511A1 (en) 2004-06-04 2005-12-22 Icos Corporation Methods for treating mast cell disorders
WO2006089106A3 (en) 2005-02-17 2006-12-07 Icos Corp Phosphoinositide 3-kinase inhibitors for inhibiting leukocyte accumulation
US20080287469A1 (en) 2005-02-17 2008-11-20 Diacovo Thomas G Phosphoinositide 3-Kinase Inhibitors for Inhibiting Leukocyte Accumulation
WO2006089106A2 (en) 2005-02-17 2006-08-24 Icos Corporation Phosphoinositide 3-kinase inhibitors for inhibiting leukocyte accumulation
WO2007076085A3 (en) 2005-12-22 2007-08-23 Prolexys Pharmaceuticals Inc Fused pyrimidones and thiopyrimidones, and uses thereof
WO2007076085A2 (en) 2005-12-22 2007-07-05 Prolexys Pharmaceuticals, Inc . Fused pyrimidones and thiopyrimidones, and uses thereof
WO2008064018A1 (en) 2006-11-13 2008-05-29 Eli Lilly & Co. Thienopyrimidinones for treatment of inflammatory disorders and cancers
WO2009046448A1 (en) 2007-10-04 2009-04-09 Intellikine, Inc. Chemical entities and therapeutic uses thereof
WO2009058361A1 (en) 2007-10-31 2009-05-07 Dynavax Technologies Corp. Inhibition of type i ifn production
WO2009088990A1 (en) 2008-01-04 2009-07-16 Intellikine, Inc. Certain chemical entities, compositions and methods
WO2009088986A1 (en) 2008-01-04 2009-07-16 Intellikine, Inc. Certain chemical entities, compositions and methods
US20100202963A1 (en) 2008-11-13 2010-08-12 Gallatin W Michael Therapies for hematologic malignancies
WO2010057048A1 (en) 2008-11-13 2010-05-20 Calistoga Pharmaceuticals Inc. Therapies for hematologic malignancies
WO2010065923A3 (en) 2008-12-04 2010-07-29 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Phosphatidylinositol-3-kinase p110 delta-targeted drugs in the treatment of cns disorders
WO2010065923A2 (en) 2008-12-04 2010-06-10 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Phosphatidylinositol-3-kinase p110 delta-targeted drugs in the treatment of cns disorders
US20100249155A1 (en) 2009-03-24 2010-09-30 Evarts Jerry B Atropisomers of 2-purinyl-3-tolyl-quinazolinone derivatives and methods of use
WO2010123931A1 (en) 2009-04-20 2010-10-28 Calistoga Pharmaceuticals Inc. Methods of treatment for solid tumors
WO2011011550A1 (en) * 2009-07-21 2011-01-27 Calistoga Pharmaceuticals Inc. Treatment of liver disorders with pi3k inhibitors
WO2011153514A2 (en) 2010-06-03 2011-12-08 Pharmacyclics, Inc. The use of inhibitors of bruton's tyrosine kinase (btk)
WO2011153514A9 (en) 2010-06-03 2012-04-05 Pharmacyclics, Inc. The use of inhibitors of bruton's tyrosine kinase (btk)

Non-Patent Citations (493)

* Cited by examiner, † Cited by third party
Title
"Acute Congestive Heart Failure", Thomas N. Levin, Postgraduate Medicine, vol. 101, No. 1, 1997.
"Cardiovascular Disease: Treatment for Stroke", Stanford Hospital & Clinics, 2003.
"Chemia Lekow", ed. E. Pawelczyk, PZWL, Warszawa 1986, see, part 1.2.2.
"Heart Disease", Charlotte E. Grayson, WebMD, 2004.
"NIH Heart Disease & Stroke Research: Fact Sheet", American Heart Association, 2004.
"Preparatyka Organiczna", ed. A.I. Vogel, WNT, Warszawa 1984, page e.g. 83.
Abramson and Shipp, Blood (2005) 106(4):1164-1174.
Abu-Duhier et al., Br. J. Haematol. (2001) 113:983-988.
Adamkiewicz, "Tumor Angiogenesis: Mechanisms" IMT Marburg-Research Group, retrieved from the internet on Apr. 13, 2004, URL: .
Adamkiewicz, "Tumor Angiogenesis: Mechanisms" IMT Marburg—Research Group, retrieved from the internet on Apr. 13, 2004, URL: <http://www.imt.uni-marburg.de/—adamkiew/mechanism.html>.
Advisory Action from U.S. Appl. No. 11/596,092, mailed on Jul. 27, 2010.
Ager et al., J. Med. Chem. (1977) 20:379-386.
Ali et al., Nature (2004) 431:1007-1011.
Alon et al., "The molecular basis of leukocyte adhesion to and migration through vascular endothelium," Mirelman et al. (eds.), Life Sciences Open Day Book 2002, Weizmann Institute of Science, Life Sciences Department, Chapter 8, vol. 2:206-207 (2002), retrieved from the internet on Sep. 2, 2005, URL: .
Alon et al., "The molecular basis of leukocyte adhesion to and migration through vascular endothelium," Mirelman et al. (eds.), Life Sciences Open Day Book 2002, Weizmann Institute of Science, Life Sciences Department, Chapter 8, vol. 2:206-207 (2002), retrieved from the internet on Sep. 2, 2005, URL: <www.weizmann.ac.ll/Biology/open—day—2002/book/ronen—alon.pdf>.
Amendment from U.S. Appl. No. 09/841,341, filed Aug. 21, 2002.
Amendment from U.S. Appl. No. 10/027,591, filed Jun. 3, 2003.
Amendment in Response to Final Office Action from U.S. Appl. No. 11/596,092, filed Jul. 19, 2010.
Amendment in Response to Non-Final Office Action / Restriction Requirement from U.S. Appl. No. 11/884,566, filed Jun. 7, 2010.
Amendment in Response to Non-Final Office Action from U.S. Appl. No. 10/918,803, filed Oct. 1, 2008.
Amendment in Response to Non-Final Office Action from U.S. Appl. No. 10/918,803, filed Sep. 4, 2009.
Amendment in Response to Non-Final Office Action from U.S. Appl. No. 11/110,204, filed Dec. 31, 2008.
Amendment in Response to Non-Final Office Action from U.S. Appl. No. 11/110,204, filed Jun. 4, 2010.
Amendment in Response to Non-Final Office Action from U.S. Appl. No. 11/110,204, filed Sep. 4, 2009.
Amendment in Response to Non-Final Office Action from U.S. Appl. No. 11/596,092, filed Mar. 24, 2010.
Amendment in Response to Non-Final Office Action from U.S. Appl. No. 11/596,092, filed Nov. 10, 2009.
Amendment Under 37 C.F.R. § 1.111 from U.S. Appl. No. 11/129,006, filed Apr. 12, 2010.
Amendment Under 37 C.F.R. § 1.111/Restriction Requirement from U.S. Appl. No. 11/110,204, filed Apr. 10, 2008.
Amendment with Request for Continued Examination from U.S. Appl. No. 11/596,092, filed Sep. 1, 2010. (8.00).
Amin et al., Circ Res (2003) 93(4):321-329.
Angel, Activities of Phosphoinositide Kinase-3 (Pl3K) (1999) retrieved from the internet on May 22, 2003, URL: http://www.chem.csustan.edu/chem4400/SJBR/angel99.htm.
Angio World, "How Angiogenesis Complicates Psoriasis" (2001) retrieved from the internet on Apr. 13, 2004, URL: .
Angio World, "How Angiogenesis Complicates Psoriasis" (2001) retrieved from the internet on Apr. 13, 2004, URL: <http://www.angioworld.com/psoriasis.htm>.
Annabi et al., J. Cell. Biochem. (2004) 91:1146-1158.
Anonymous. (2004). "NIH Heart Disease & Stroke Research: Fact Sheet", American Heart Association, located at <http://www.americanheart.org/presenter.jhtml?identifier=3010188>, last visited Feb. 17, 2004, 1 page.
Anonymous. (2006). "Cardiovascular Disease: Treatment for Stroke", Stanford Hospital & Clinics, located at <httpL//www.stanfordhospital.com/healthLib/atoz/cardiac/stktreat.html>, last visited on Sep. 19, 2006, 2 pages.
Anonymous. (2006). "Heart Disease", WebMD, located at <http://www.wedmd.com/content/pages/9/1675—57842.htm> as retrieved on Sep. 14, 2006, 1 page.
Anonymous. (2010) "Systemic Lupus Erythematosus", located at <http://www.nim.nih.gov/medlineplus/ency/articie/000435.htm>, last visited Aug. 1, 2010, 4 pages.
Anonymous. (2010). "Multiple Sclerosis", located at <http://www.health.nytimes.com/health/guides/disease/multiple-sclerosis/overview.html>, last visited Aug. 1, 2010, 4 pages
Anonymous. (2010). "Spinal Cord Injury", located at <http://www.medicinenet.com/spinal—cord—injury/page5.htm>, last visited on Aug. 1, 2010, 3 pages.
Anonymous. (Mar. 16, 2010). "Study to Investigate CAL-101 in Combination with Chemotherapeutic Agents and CD20 mAb in Patients with Relapsed and Rituximab or Refractory Indolent B-Cell Non-Hodgkin's Lymphoma, Mantle Cell Lymphoma or Chronic Lymphocytic Leukemia," <http://clinicaltrials.gov/ct2/show/study/NCT01088048>, last visited Jul. 24, 2012, 4 pages.
Anonymous. (Sep. 16, 2010). "A Phase 2 Single Arm Study to Investigate the Safety and Clinical Activity of CAL-101 in Combination with Rituximab in Elderly Patients with Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma," located at <http://clinicaltrials.gov/archive/NCT01203930/2010—09—16>, last visited Jul. 24, 2012, 4 pages.
Aoki et al., PNAS USA (2001) 98:136-141.
Aoudjit et al., J. Immunol. (1998) 161:2333-2338.
Arcaro et al., Biochem. J. (1994) 298:517-520.
Asti et al., Pulm. Pharmacol. Ther. (2000) 13:61-69.
Ausprunk et al., Microvasc. Res. (1977) 14:53-65.
Bader, A.G. et al. (2005). "Oncogenic P13K Deregulates Transcription and Translation," Nature Reviews Cancer 5(12):921-922 (abstract and introduction).
Barakat et al., Chemical Abstracts (1996) 124(21):1334.
Barakat, S.E-S. et al. (Dec. 1994). "Synthesis and CNS Depressant Activity of Some New Quinazoline Derivatives," Az. J. Pharm. Sci. 14:239-246.
Bardet et al., 9th Congress of the European Hematology Association Geneva Palexpo, Switzerland, Jun. 10-13, 2004, View Abstract data, Abstract nr.: 620.
Barker, Lancet (1991) 338:227-230.
Benekli et al., Blood (2002) 99:252-257.
Benekli et al., Blood (2003) 101:2940-2954.
Bennett et al., Ann. Intern. Med. (1985) 103:620-625.
Bennett et al., J. Pharmacol. Exp. Ther. (1997) 280:988-1000.
Berge et al., J. Pharm. Sci. (1977) 66:1.
Bergers et al., Science (1999) 284:808-812.
Bharadwaj et al., J. Immunol. (2001) 166:6735-6741.
Binetruy-Tournaire et al., EMBO J. (2000) 19:1525-1533.
Bloemen et al., Am. J. Respir. Crit. Care Med. (1996) 153:521-529.
Boehm et al., Nature (1997) 390:404-407.
Borregaard et al., Blood (1997) 89:3503-3521.
Boudewijn et al., Nature (1995) 376:599-602.
Bouscary et al., Blood (2003) 101:3436-3443.
Bouscary et al., Oncogene (2001) 20:2197-2204.
Bowes et al., Exp. Neurol. (1993) 119:215-219.
Brennan et al., Arthritis Res. (2002) 4(Suppl. 3):S177-S182.
Brown et al., 44th Annual Meeting of the American Society of Hematology, Philadelphia, PA, Dec. 6-10, 2002, Abstract No. 3012, p. 761A.
Brown, J. et al. (2010). "Clinical Activity in a Phase 1 Study of Cal-101, an Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase P110Delta, in Patients with B-Cell Malignancies," Haematologica 95(s2):466, Abstract No. 1130.
Brunn et al., EMBO J. (1996) 15:5256-5267.
Burger, J.A. et al. (Dec. 12, 2008). "High-Level Expression of the T-Cell Chemokines CCL3 and CCL4 by Chronic Lymphocytic Leukemia B Cells in Nurselike Cell Cocultures and after BCR Stimulation," Blood 113(13):3050-3058.
Burgering, B.M. et al. (Aug. 17, 1995). "Protein Kinase B (c-Akt) in Phosphatidylinositol3-Oh Kinase Signal Transduction," Nature376:599-602.
Burkle, A. et al. (Nov. 1, 2007). "Overexpression of the CXCR5 Chemokine Receptor, and its Ligand, CXCL13 in B-Cell Chronic Lymphocytic Leukemia," Blood 110(9): 3316-3325.
Butcher et al., Science (1996) 272:60-66.
Cadwallader et al., J. Immunol. (2002) 169:3336-3344.
Cantley et al., PNAS USA (1999) 96:4240-4245.
Cantley et al., Science (2002) 296:1655-1657.
Cardone et al., Science (1998) 282:1318-1321.
Carnero et al., FEB Letters (1998) 422:155-159.
CAS Abstract, Accession No. DN 86:83505 [1977] pp. 112-118.
Castillo, J.J. et al. (Jan. 2012). "CAL-101: A Phosphatidylinositol-3-Kinase p110-Delta Inhibitor for the Treatment of Lymphoid Malignancies," Expert Opinion on Investigational Drugs 21(1): 15-22.
Cebon et al., Cancer Immun. (2003) 3:7-25.
Chang et al., Exp. Opin. Ther. Patents (2001) 11:45-59.
Chang, BioMed. Eng. Online (2003) 2:12.
Chantry et al., J. Biol. Chem. (1997) 272:19236-19241.
Chen et al., Blood (2000) 96:3181-3187.
Chern et al., Chem. Pharm. Bull. (1998) 46(6):928-933.
Chern et al., Chemical Abstracts (1998) 129(16):676.
Cheson et al., The New England Journal of Medicine(2008) 359(6):613-626.
Chiba, K. et al. (Jun. 1, 2009). "Multiple Osteolytic Bone Lesions with High Serum Levels of Interleukin-6 and CCL Chemokines in a Patient with Adult T Cell Leukemia," International Journal of Laboratory Hematology31(3):368-371.
Chopp et al., Stroke (1994) 25:869-876.
Choy et al., Arthritis & Rheumatism (2002) 46:3143-3150.
Clark et al., J. Neurosurg. (1991) 75:623-627.
Clavel et al., Joint Bone Spine (2003) 70:321-326.
Clayton et al., J. Exp. Med. (2002) 196:753-763.
Cleary, J.M. et al. (2010). "Development of Phosphoinositide-3 Kinase Pathway Inhibitors for Advanced Cancer," Curr. Oncol. Rep. 12:87-94.
Coligan et al., Current Protocols in Protein Science (2002) 3:15-20.
Constantin et al., Immunity(2000) 13:759-769.
Cosimi et al., J. Immunol. (1990) 144:4604-4612.
Coxon, Immunity (1996) 5:653-666.
Creamer et al., Angiogenesis (2002) 5:231-236.
Cross et al., Inflamm. Res. (1999) 48:255-261.
Curnock et al., Immunology (2002) 105:125-136.
Dahia et al., Hum. Mol. Genet. (1999) 8:185-193.
Dallegri et al., Inflamm. Res. (1997) 46:382-391.
Das et al., Prog. Retin. Eye Res. (2003) 22:721-748.
Datta et al., Cell (1997) 91:231-241.
Datta et al., Genes & Dev. (1999) 13:2905-2927.
Davies et al., Biochem. J. (2000) 351:95-105.
De Benedetti et al., Clin. Exper. Reheum. (1992) 10:493-498.
Deininger et al., Blood (2000) 96:3343-3356.
Demeester et al., Transplantation (1996) 62:1477-1485.
Descamps et al., J. Immunol. (2004) 173:4953-4959.
Devos, S. et al. (Nov. 2011). "A Phase 1 Study of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3K) Inhibitor, CAL-101 (GS-1101), in Combination with Rituximab and/or Bendamustine in Patients with Previously Treated, Indolent Non-Hodgkin Lymphoma (iNHL)," Blood 118(21):1160.
Doggett et al., Biophys. J. (2002) 83:194-205.
Dorland's Illustrated Medical Dictionary (2003), retrieved Oct. 21, 2005 from Xreferplus, http://www.xreferplus.com/entry/4196914.
Downward, Nature (1995) 376:553-554.
Drakesmith et al., Immunol. Today (2000) 21:214-217.
Druker et al., New England Journal of Medicine (2001) 344:1038-1042.
Dunne et al., Blood (2002) 99:336-341.
Edwards et al., Canc. Res. (2002) 62:4671-4677.
Eichholtz et al., J. Biol. Chem. (1993) 268:1982-1986.
Eisenkraft, A. et al. (Oct. 1, 2006, e-published Mar. 3, 2006). "MCP-1 in the Cerebrospinal Fluid of Children with Acute Lymphoblastic Leukemia," Leukemia Research30(10): 1259-1261.
El-Fattah et al., Indian J Hetercyclic Chemistry (1995) 4:199-202.
El-Feky et al., Chemical Abstracts (1987) 106(13):650.
El-Feky et al., Chemical Abstracts (1999) 131(23):497.
El-Feky, S.A. (Aug. 1998). "Novel Quinazolinones From 2-Cyanomethyl-3-Phenyl-4(3H) Quinazolinone," Bollettino Chimico Farmaceutico 137(7):286-289.
El-Feky, S.A. et al. (1985). "Synthesis of Certain New Sulfur-Containing Quinazolinone Derivatives Likely to Possess CNS Depressant Action," Egyptian Journal of Pharmaceutical Sciences24(1-4):39-47.
Engelman et al., Nature Reviews (2006) 7:606-619.
Environmental Protection Agency, EPA-Radiation Information (EPA's Radiation Protection Program:Information) "Ionizing Radiation Fact Sheet Series No. 1" (May 1998) Retrieved on Apr. 21, 2004: http://www.epa.gov/radiation/docs/ionize/ionize.htm.
Erbagci et al., Clin. Biochem. (2001) 34:645-650.
Estey, Cancer (2001) 92:1059-1073.
Etzioni, Pediatr. Res. (1996) 39:191-198.
European Search Report mailed Mar. 29, 2011, for EP Patent Application No. 10163434.3, filed on Apr. 24, 2001, 9 pages.
Faffe et al., Eur. Respir. J. (2000) 15:85-91.
Fantl et al., Ann. Rev. Biochem. (1993) 62:453-481.
Faust et al., Blood (2000) 96:719-726.
Final Office Action from U.S. Appl. No. 10/918,803, mailed on Jan. 8, 2009.
Final Office Action from U.S. Appl. No. 11/129,006, mailed on Oct. 5, 2010.
Final Office Action from U.S. Appl. No. 11/596,092, mailed on May 18, 2010.
Final Office Action mailed on Feb. 15, 2012, for U.S. Appl. No. 12/732,124, filed Mar. 25, 2010, 12 pages.
Final Office Action mailed on Jun. 7, 2012, for U.S. Appl. No. 11/129,006, filed May 12, 2005, 14 pages.
Final Office Action mailed on Oct. 24, 2011, for U.S. Appl. No. 12/732,128, filed Mar. 25, 2010, 8 pages.
First Preliminary Amendment from U.S. Appl. No. 12/538,748, filed Apr. 1, 2010.
Flinn, I.W. et al. (2009). "Preliminary Evidence of Clinical Activity in a Phase 1 Study of CAL-101, a Selective Inhibitor of the p1108 Isoform of Phosphatidylinositol 3-Kinase (P13K), in Patients with Select Hematologic Malignancies," Journal of Clinical Oncology 27:156s, Abstract 3543.
Flinn, I.W. et al. (Nov. 20, 2009). "Evidence of Clinical Activity in a Phase 1 Study of CAL-101, an Oral P110Δ Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase, in Patients with Relapsed or Refractory B-Cell Malignancies," Blood 114(22):380, Abstract 922.
Flinn, I.W. et al. (Nov. 2010). "A Phase 1 Study of CAL-101, An Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase P110 Delta, in Combination with Rituximab and/or Bendamustine in Patients with Relapsed or Refractory B-Cell Malignancies," Blood 116(21):1168.
Flinn, W. et al. (Jun. 4-7, 2009). "Preliminary Evidence of Clinical Activity in a Phase 1 Study of CAL-101, A Potent Selective Inhibitor of the P110Delta Isoform of Phosphatidylinositol 3-Kinase, in Patients with B-Cell Maglignancies," Haematologica 94(s2):303, Abstract 0744.
Folkman, Curr. Mol. Med. (2003) 3:643-651.
Folkman, Nat. Med. (1995) 1:27-31.
Fraser et al., Science(1991) 251:313-316.
Frey et al., Lancet (2008) 372(9643):1088-1099 (abstract).
Freyssinier et al., Br. J. Haematol. (1999) 106:912-922.
Fruman et al., Ann. Rev. Biochem. (1998) 67:481-507.
Fruman et al., Semin. Immunol. (2002) 14:7-18.
Furman, R.R. (Jul. 2010). "New Agents in Early Clinical Trials for CLL Therapy," Clinical Advances in Hematology & Oncology 8(7):475-476.
Fuwa et al., Tetrahedron (2005) 61:4297-4312.
Garcia-Barros et al., Science (2003) 300:1155-1159.
Genbank Accession No. AK040867, last updated Sep. 19, 2008, located at <http://www.ncbi.n1m.nih.gov.nuccore/26334014>, last visited on Apr. 16, 2010, 6 pages.
GenBank Accession No. AR255866, last updated Dec. 20, 2002, located at <http://www.ncbi.n1m.nih.gov.nuccore/27305059>, last visited on Apr. 16, 2010, 2 pages.
GenBank Accession No. BC035203, last updated Aug. 11, 2006, located at <http://www.ncbi.n1m.nih.gov/nuccore/23270986>, last visited on Apr. 16, 2010, 5 pages.
GenBank Accession No. NM—005026, last updated Apr. 11, 2010, located at <http://www.ncbi.n1m.nih.gov/nuccore/15654404>, last visited Apr. 16, 2010, 7 pages.
GenBank Accession No. NM—008840, last updated on Mar. 5, 2010, located at <http://www.ncbi.n1m.nih.gov/nuccore/255708435>, last visited on Apr. 16, 2010, 5 pages.
GenBank Accession No. U57843, last updated on May 9, 1997, located at <http://www.ncbi.n1m.nih.gov/nuccore/U57843>, last visited on Aug. 9, 2011, 2 pages.
GenBank Accession No. U86453, last updated on Jul. 7, 1998, located at <http://www.ncbi.n1m.nih.gov/nuccore/2317893>, last visited on Apr. 16, 2010, 3 pages.
GenBank Accession No. U86587, last updated Jul. 7, 1998, located at <http://www.ncbi.nlm.nih.gov/nuccore/2331237>, last visited on Apr. 16, 2010, 3 pages.
GenBank Accession No. XM—345606, last updated Jun. 22, 2006, located at <http://www.ncbi.n1m.nih.gov/nuccore/109475856?report=genbank>, last visited on Apr. 16, 2010, 3 pages.
GenBank Accession No. Y10055, last updated Oct. 7, 2008, located at <http://www.ncbi.n1m.nih.gov/nuccore/37496958>, last visited on Apr. 16, 2010, 3 pages.
Geng et al., Cancer Research (2001) 61:2413-19.
Geng et al., Cancer Research (2004) 64:4893-4899.
Geng et al., Cancer Research (2004) 64:8130-8133.
Gibson, (ed.), Antisense and Ribozyme Methodology, "Laboratory Companion" (1997) Table of Contents.
Gilliland et al., Blood (2002) 100:1532-1542.
Gilliland et al., Cancer Cell (2002) 1:417-420.
Gingras et al., Genes Dev. (2001) 15:2852-2864.
Gingras et al., Genes Dev. (2001) 15:807-826.
Glenjen et al., Int. J. Cancer (2002) 101:86-94.
Gorczynski et al., J. Immunol. (1994) 152:2011-2019.
Gorski et al., Cancer Research (1999) 59:3374-3378.
Gouilleux-Gruart et al., Blood (1996) 87:1692-1697.
Grant et al., Drugs of Today (2002) 38:783-791.
Gross et al., Science (1998) 281:703-706.
Gu et al., Mol. Cell. Biol. (2000) 20:7109-7120.
Gupta et al., Int'l J Radiation Oncology Biology Physics (2003) 56(3):846-853.
Gute et al., Mol. Cell. Biochem. (1998) 179:169-187.
Guzman et al., Blood (2001) 98:2301-2307.
Guzman et al., Proc. Natl. Acad. Sci. (USA) (2002) 99:16220-16225.
Hadden, Int. Immunopharmacol. (2003) 3:1061-1071.
Hallahan et al., Proc. Natl. Acad. Sci (USA) (1997) 94:6432-6437.
Halloran et al., Arthritis Rheum. (1996) 39:810-819.
Hanamoto et al., Am. J. Pathol. (2004) 164(3):997-1006.
Hannigan et al., Proc. Natl. Acad. Sci. U.S.A. (2002) 99:3603-3608.
Hardma et al. (eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics (1996) 9th ed., pp. 11-16.
Harlan, Haematology 96, the Education Program Book of the 26th Congress of the International Society of Haematology. Singapore, 1996.
Harning et al., Transplantation (1991) 52:842-845.
Hartley et al., Cell (1995) 82:849-856.
Hartman et al., Cardiovasc. Res. (1995) 30:47-54.
Hasagawa et al., Int. Immunol. (1994) 6:831-838.
Hassan et al., Chinese Journal of Chemistry (1991) 9:262-269.
Hattori, H. et al. (May/Jun. 2010). "Reactive Oxygen Species as Signaling Molecules in Neutrophil Chemotaxis," Communicative and Integrative Biology 3(3):278-281.
Hattori, N. et al. (May 1, 2010). "Over-Expression of CCL3??MIP-1[Alpha] in a Blastoid Mantle Cell Lymphoma with Hypercalcemia," European Journal of Haematology84(5):448452.
He et al., Opthalmol. Vis. Sci. (1994) 35:3218-3225.
Healy et al., Hum. Reprod. Update (1998) 4:736-740.
Healy et al., Pharma. Res. (Dec. 2004) 21:2234-2246.
Heit et al., J. Cell Biol. (2002) 159:91-102.
Hellman, Cancer: Principles and Practice of Oncology (1993) 4th ed., vol. 1:248-275.
Herman, S.E.M. et al. (Mar. 4, 2011). "The Role of Phosphatidylinositol 3-Kinase-Delta in the Immunomodulatory Effects of Lenalidomide in Chronic Lymphocytic Leukemia," Blood 117(16):4323-4327.
Herman, S.E.M. et al. (Sep. 23, 2010). "Phosphatidylinositol 3-Kinase-δ Inhibitor CAL-101 Shows Promising Preclinical Activity in Chronic Lymphocytic Leukemia by Antagonizing Intrinsic and Extrinsic Cellular Survival Signals," Blood 116(12):2078-2088.
Herold et al., Cell Immunol. (1994) 157:489-500.
Higuchi, Prodrugs as Novel Delivery Systems, vol. 14, ASCD Symposium Series, and in Roche (ed.), Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987) Chapter 1, pp. 1-12.
Hilbert et al., J. Exper. Med. (1995) 182:243-248.
Hiles et al., Cell (1992) 70:419-429.
Hilmas et al., Rad. Res. (1975) 61:128-143.
Hirsch et al., Science (2000) 287:1049-1053.
Hoellenriegel, J. et al. (Jul. 29, 2011). "The Phosphoinositide 3′-Kinase Delta Inhibitor, CAL-101, Inhibits B-Cell Receptor Signaling and Chemokine Networks in Chronic Lymphocytic Leukemia," Blood 118(13): 3603-3612.
Hoellenriegel, J. et al. (Nov. 2010). "Phosphoinositide 3′-Kinase (PI3K) Delta Inhibition with CAL-101 Blocks B-Cell Receptor (BCR) Signaling and the Prosurvival Actions of Nurselike Cells (NLC), in Chronic Lymphocytic Leukemia," Blood 116(21):27-28.
Horgan et al., Am. J. Physiol. (1991) 261:H1578-H1584.
Hsieh, S.N. (2003). "Identification of PI3Kγ in Endothelial Cells and Its Involvement in Sphingosine 1-Phosphate Mediated Endothelial Cell Migration," Dissertation, Friedrick Schiller University, Jena, Germany, 104 pages.
Hu et al., Mol. Cell. Biol. (1993) 13:7677-7688.
Hu et al., Science (1995) 268:100-102.
Hunter, Cell(1995) 83:1-4.
Hussong et al., Blood (2000) 95:309-313.
Ikeda, H. et al. (Feb. 2009). "CAL-101: A Selective Inhibitor of P13K p110δ for the Treatment of Multiple Myeloma," Clinical Lymphoma and Myeloma 9(Supp. 1):S98-S99.
Ikeda, H. et al. (Nov. 16, 2008). "CAL-101, a Specific Inhibitor of the p110δ Isoform of Phosphatidylinositide 3-Kinase Induces Cytotoxicity in Multiple Myeloma (MM)," Blood 112(11):950, Abstract No. 2753.
Ikeda, H. et al. (Sep. 2, 2010). "Pl3K/p110δ is a Novel Therapeutic Target in Multiple Myeloma," Blood 116(9):1460-1468.
International Preliminary Report on Patentability for PCT/US2006/005621, issued on Aug. 21, 2007, 8 pages.
International Preliminary Report on Patentability for PCT/US2010/028554, mailed on Oct. 6, 2011, 6 pages.
International Preliminary Report on Patentability mailed on Jan. 24, 2012, for PCT Application No. PCT/US2010/042801, filed on Jul. 21, 2010, 14 pages.
International Search Report and Written Opinion for PCT/US2010/028554, mailed Jul. 28, 2010, 8 pages.
International Search Report for International (PCT) Patent Application Serial No. PCT/US2004/026436, dated Dec. 2, 2004.
International Search Report for International (PCT) Patent Application Serial No. PCT/US2004/029561, dated May 25, 2005.
International Search Report for International (PCT) Patent Application Serial No. PCT/US2004/037860, dated May 6, 2005.
International Search Report for International (PCT) Patent Application Serial PCT/US2004/026834, dated Nov. 29, 2004.
International Search Report for PCT/US2009/064471, mailed on Feb. 12, 2010, 4 pages.
International Search Report mailed on Aug. 29, 2005, for PCT Application No. PCT/US2005/016778, filed on May 12, 2005, 4 pages.
International Search Report mailed on Aug. 29, 2011, for PCT Application No. PCT/US2011/040051, filed Jun. 10, 2011, 6 pages.
International Search Report mailed on Dec. 5, 2011, for PCT Application No. PCT/US2011/053102, filed on Sep. 23, 2011, 4 pages.
International Search Report mailed on Jun. 14, 2012 for PCT Application No. PCT/US2012/028654, filed on Mar. 9, 2012, 7 pages.
International Search Report mailed on Oct. 22, 2010 for PCT Application No. PCT/US2010/042801, filed on Jul. 21, 2010, 8 pages.
International Search Report mailed on Sep. 15, 2006 for PCT Application No. PCT/US2006/005621, filed on Feb. 16, 2006, 4 pages.
Interview Summary from U.S. Appl. No. 10/918,825, mailed on Jun. 14, 2006.
Ismail and Sayed, Indian Journal of Chemistry(1982) 21B(5):461-462.
Ismail et al., Chemical Abstracts (1983) vol. 98, No. 1, p. 406.
Isobe et al., Science (1992) 255:1125-1127.
Jares et al., Nat. Rev. Cancer(2007) 7(10):750-762.
Johnson et al., Intl. J. Rad. One. Biol. Phys. (1976) 1:659-670.
Johnson et al., J. Endourol. (2003) 17:557-562.
Jordan, Nature Reviews: Drug Discovery(2003) 2:205-213.
Jou et al., Mol. Cell. Biol. (2002) 22:8580-8591.
Kahl, B.S. (May 2010). "Novel Agents for Non-Hodgkin Lymphoma," Clinical Advances in Hematology & Oncology 8(5)(Suppl. 10):10-12.
Kakimoto et al., Cell. Immunol. (1992) 142:326-337.
Kallman et al., Canc. Res. (1972) 32:483-490.
Kandel et al., Exp. Cell Res. (1999) 253:210-229.
Kawasaki et al., J. Immunol. (1993) 150:1074-1083.
Kim et al., Endocrin. (2000) 141:1846-1853.
Kim, Retrieved from the Internet on Apr. 13, 2004: URL: http://www.math.umn.edu/˜yjkim/biopaper/timy,html.
Kishimoto et al., Cell (1987) 50:193-202.
Klein et al., Cell. Signal. (2001) 13:335-343.
Klippel et al., Mol. Cell. Biol. (1994) 14:2675-2685.
Knall et al., Proc. Natl. Acad. Sci. (USA) (1997) 94:3052-3057.
Knight and Shokat, Chemistry and Biology (2005) 12:621-637.
Knight et al., Bioorganic & Medicinal Chemistry (Jul. 2004) 12:4749-4759.
Knoerzer et al., Toxicol. Pathol. (1997) 25:13-19.
Kolonin et al., Nature Medicine (2004) 10:625-632.
Kong et al., J. Biol. Chem. (2000) 275:36035-36042.
Kopf et al., Nature (1994) 368:339-342.
Krugmann et al., J. Biol. Chem. (1999) 274:17152-17158.
Kumar et al., Blood (2003) 101(10):3960-3968.
Kunkel et al., Circ. Res. (1996) 79:1196-1204.
Lannutti, B.J. et al. (Apr. 2009). "CAL-101, a Specific PI3K p110δ Inhibitor for the Treatment of Hematological Maglignancies," Proceedings of the American Association for Cancer Research 50:1400, Abstract No. #SY32-2.
Lannutti, B.J. et al. (Nov. 16, 2008). "CAL-101, a Potent Selective Inhibitor of the p110d Isoform of Phosphatidylinositol 3-Kinase, Attenuates PI3K Signaling and Inhibitos Proliferation and Survival of Acure Lumpoblastic Leukemia in Addition to a Range of Other Hematological Malignancies," Blood 112(11):12, Abstract No. 16.
Lannutti, B.J. et al. (Nov. 20, 2009). "CAL-101, An Oral P110δ Selective Phosphatidylinositol-3-Kinase (PI3K) Inhibitor for the Treatment of B Cell Malignancies Inhibits PI3K Signaling, Cellular Viability and Protective Signals of the Microenvironment," Blood 114(22):120-121, Abstract No. 286.
Lannutti, J. et al. (2010). "Demonstration of Pharmacodynamic Target Inhibition and Chemokine Modulation in Patients with CLL Following Treatment with CAL-101, a Selective Inhibitor of the P110 Delta Isoform of PI3K," Haematologica 95(S2):45-46, Abstract No. 0113.
Lannutti, J. et al. (Jun. 4-7, 2009). "CAL-101, A Specific Inhibitor of the P11-Delta Isoform of Phosphatidylinositide 3-Kinase, for the Treatment of Non-Hodgkins Lymphomas," Haematologica 94(S2):272-273, Abstract No. 0668.
Lecoq-Lafon et al., Blood (1999) 93:2578-2585.
Lee et al., FASEB J. (2006) 20:455-465.
Lemmon et al., Trends Cell. Biol. (1997) 7:237-242.
Letter from Polish Patent Law Firm "Patpol" translating Office Action from Polish Patent Application No. P-358590, dated Feb. 27, 2008.
Li et al., Trends Biochem. Sci. (Jan. 2004) 29:32-38.
Liang et al., Molecular Cancer Therapeutics (2003) 2(4):353-360.
Liekens et al., Biochem. Pharmacol. (2001) 61:253-270.
Liu et al., J. Immunol. (Jan. 2004) 172 :7-13.
Lowell et al., J. Cell Biol. (1996) 133:895-910.
Luo et al., Cancer Cell (2003) 4:257-262.
Luo et al., Leukemia (2003) 17:1-8.
Luster, N. Engl. J. Med. (1998) 338:436-445.
Madge et al., J. Biol. Chem. (2000) 275:15458-15465.
Manning et al., Mol. Cell (2002) 10:151-162.
Marchione, M. et al. (2006). "Drugs hold promise in kidney cancer fight", located at <http://www.ledger-enquirer.com/mld/ledgerenquirer/living/health/14744763.htm, last visited on Sep. 2, 2006, 3 pages.
Marley et al., Br. J. Haematol. (May 2004) 125:500-511.
May, S.E. et al. (Nov. 16, 2008). "CAL-101, a Selective Inhibitor of the p110δ Isoform of Phosphatidylinositol 3-Kinase, Effectively Induces Apoptosis in Primary Chronic Lumphocytic Leukemia Cells Providing a Novel Therapeutic Strategy for the Treatment of this Disease," Blood 112(11):1085-1086, Abstract No. 3165.
Mazur, G. et al. (Jan. 1, 2007). "Increased Monocyte Chemoattractant Protien 1 (MCP-1/CCL-2) Serum Level in Acute Myeloid Leukemia," Neoplasma54(5):285-289.
Meneses et al., Gene Ther. (2001) 8:646-648.
Milella et al., J. Clin. Invest. (2001) 108:851-859.
Miller et al., Nucleic Acids Res. (1988) 16:1215.
Moehler et al., Ann. Hematol. (2001) 80:695-705.
Moore, J. Clin. Invest. (2002) 109:313-315.
Mori, N. (Sep. 10, 2004). "Elevated Expression of CCL5/RANTES in Adult T-Cell Leukemia Cells: Possible Transactivation of the CCL5 Gene by Human T-Cell Leukemia Virus Type I Tax," International Journal of Cancer111(4): 548-557.
Morton et al., Blood(2006) 107(1):265-276.
Moulton et al., Circ. (1999) 99:1726-1732.
Mulligan et al., J. Immunol. (1995) 154:1350-1363.
Mulligan et al., Proc. Natl. Acad. Sci. (USA) (1993) 90:11523-11527.
Nagase et al., Am. J. Respir. Crit. Care Med. (1996) 154:504-510.
Nakao et al., Leukemia (1996) 10:1911-1918.
Nakao et al., Muscle Nerve (1995) 18:93-102.
Neshat et al., Proc. Natl. Acad. Sci. (USA) (2001) 98:10314-10319.
Newell et al., J. Chem. Soc., Perkin Trans (2001) 2:961-963.
Niens, M. et al. (Mar. 1, 2008). "Serum Chemokine Levels in Hodgkin Lymphoma Patients: Highly Increased Levels of CCL17 and CCL22," British Journal of Haematology140(5):527-536.
Ninomiya et al., J. Biol. Chem. (1994) 269:22732-22737.
Non Final Office Action from U.S. Appl. No. 11/596,092, mailed on Dec. 24, 2009.
Non-Final Office Action from U.S. Appl. No. 09/841,341, mailed on Apr. 25, 2002.
Non-Final Office Action from U.S. Appl. No. 10/027,591, mailed on Feb. 26, 2003.
Non-Final Office Action from U.S. Appl. No. 10/918,803, mailed on Apr. 1, 2008.
Non-Final Office Action from U.S. Appl. No. 10/918,803, mailed on Mar. 16, 2010.
Non-Final Office Action from U.S. Appl. No. 10/918,825, mailed on Nov. 7, 2005.
Non-Final Office Action from U.S. Appl. No. 11/110,204, mailed on Aug. 5, 2008.
Non-Final Office Action from U.S. Appl. No. 11/110,204, mailed on Feb. 4, 2010.
Non-Final Office Action from U.S. Appl. No. 11/110,204, mailed on Jun. 17, 2009.
Non-Final Office Action from U.S. Appl. No. 11/129,006, mailed on Dec. 15, 2009.
Non-Final Office Action from U.S. Appl. No. 11/596,092, mailed on Jun. 10, 2009.
Non-Final Office Action from U.S. Appl. No. 11/884,566, mailed on Aug. 3, 2010.
Non-Final Office Action mailed on Jan. 20, 2012 for U.S. Appl. No. 13/163,597, filed Jun. 17, 2011, 14 pages.
Non-Final Office Action mailed on Jun. 28, 2011, for U.S. Appl. No. 12/732,124, filed Mar. 25, 2010, 11 pages.
Non-Final Office Action mailed on Oct. 17, 2011 for U.S. Appl. No. 12/732,124, filed Mar. 25, 2010, 8 pages.
Notice of Allowance from U.S. Appl. No. 09/841,341, mailed on Oct. 7, 2002.
Notice of Allowance from U.S. Appl. No. 10/027,591, mailed on Jul. 29, 2003.
Notice of Allowance from U.S. Appl. No. 10/337,192, mailed on Mar. 11, 2004.
Notice of Allowance from U.S. Appl. No. 10/697,912, mailed on Dec. 30, 2004.
Notice of Allowance mailed on Nov. 8, 2010, for U.S. Appl. No. 11/110,204, filed Apr. 20, 2005, 6 pages.
Notice of Reexamination for Chinese Patent Application No. 0811654.X, mailed Nov. 5, 2009; 7 pages.
Notice Regarding Non-Compliant Amendment from U.S. Appl. No. 10/918,803, mailed on Nov. 19, 2009.
Notification of Reasons for Rejection for Japanese Patent Application No. 2003-537642, mailed on May 26, 2009, 4 pages.
Office Action for European Patent Application No. 04 816 855.3, mailed on Oct. 21, 2008, 4 pages.
Ohno-Matsui et al., Invest. Ophthalmol. Vis: Sci. (2003) 44:5370-5375.
Okada, Y. et al. (Mar. 15, 2004). "Macrophage Inflammatory Protein-1[Alpha] Induces Hypercalcemia in Adult T-Cell Leukemia," Journal of Bone and Mineral Research19(7):1105-1111.
Oki, "Recent Advances in Atropisomerism" Topics in Stereochemistry (1983) 14:1-81.
Okkenhaug et al., Science (2002) 297:1031-1034.
Olsnes, A.M. et al. (Jul. 1, 2006). "T Lymphocyte Chemotactic Chemokines in Acute Myelogenous Leukemia (AML): Local Release by Native Human AML Blasts and Systemic Levels of CXCL10 (IP-10), CCL5 (RANTES) and CCL17 (TARC)," Cancer Immunology, Immunotherapy55(7):830-840.
Oppenheimer-Marks et al., J. Clin. Invest. (1998) 101:1261-1272.
Oshiro et al., Stroke (1997) 28:2031-2038.
Otsu et al., Cell (1991) 65:91-104.
Paez et al., Frank (ed.), Cancer Treatment and Research (2003) 115:146 Kluwer Academic Publishers.
Pages et al., Nature (1994) 369:327-329.
Palanki, Curr. Med. Chem. (2002) 9:219-227.
Paleolog et al., Angiogenesis (1998/1999) 2:295-307.
Panayotou et al., Trends in Cell Biol. (1992) 2:358-360.
Panes et al., Gastroenterology (1995) 108:1761-1769.
Parasharya and Parikh, J. Inst. Chemists (1992) 64(5):184-185.
Parasharya et al., Chemical Abstracts (1994) vol. 121, No. 9, p. 1065.
Park, S. et al. (2010). "Role of the PI3K/AKT and mTOR Signaling Pathways in Acute Myeloid Leukemia," Haematologica 95(5):819-829.
Parker, Current Biology (1995) 5:577-579.
Passegue et al., Proc. Natl. Acad. Sci., (USA) (2003) 100 Supp. 1:11842-11849.
Patani, G.A. et al. (1996), "Bioisosterism: A Rational Approach in Drug Design," Chem Rev. 96(8):3147-3176.
Pierce et al., J. Biol. Chem. (1997) 272:21096-21103.
Pietersz et al., Immunol. Rev.(1992) 129:57-80.
Plows et al., J. Immunol. (1999) 162(2):1018-1023.
Podsypanina et al., Proc. Natl. Acad. Sci. (USA) (2001) 98:10320-10325.
Prescott, (ed.), Methods in Cell Biology, vol. XIV, p. 33, Academic Press, New York (1976).
Psychoyos et al., J. Immunol. Methods (1991) 137:37-46.
Puri et al., Blood (2005) 106(1):150-157, 144.
Puri et al., Blood (May 2004) 103:3448-3456.
Puri, K. et al. (Jul. 18-23, 2004). "A Role for Phosphoinositide 3-Kinase δ in Neutrophil Trafficking," Immunology 2004: Cytokine Network, Regulatory Cells, Signaling, and Apoptosis: Collection of Free Papers Presented at the 12th International Congress of Immunology and 4th Annual Conference of FOCIS Medimond International Proceedings in Montreal, Canada on Jul. 18, 23, 2004, pp. 303-307.
Quirici et al., Br. J. Haematol. (2001) 115:186-194.
Rameh et al., Cell (1995) 83:821-830.
Rameh et al., J. Biol. Chem. (1999) 274:8347-8350.
Rathman et al., J. Org. Chem. (1980) 45:2169-2176.
Reeder, C.B. et al. (Oct. 26, 2010). "Novel Therapeutic Agents for B-Cell Lymphoma: Developing Rational Combinations," Blood 117(5): 1453-1462.
Remington's Pharmaceutical Sciences (1990) 18th Ed., Chapter 89, pp. 1435-1712 Table of Contents Only.
Ren et al., Curr. Drug Targets Inflamm. Allergy (2003) 2(3):242-256.
Request for Continued Examination and Amendment Under 37 C.F.R. § 1.116 from U.S. Appl. No. 10/918,803, filed May 7, 2009.
Response to Election of Species Requirement from U.S. Appl. No. 10/918,803, filed Jun. 27, 2007 (5.00).
Response to Non-Final Office Action filed on Sep. 16, 2010, for U.S. Appl. No. 10/918,803, filed Aug. 13, 2004, 25 pages.
Response to Non-Final Office Action from U.S. Appl. No. 10/918,803, filed Dec. 18, 2009.
Response to Restriction Requirement from U.S. Appl. No. 10/918,803, filed Jan. 4, 2008.
Response to Restriction Requirement from U.S. Appl. No. 11/129,006, filed May 12, 2009.
Response to Restriction Requirement from U.S. Appl. No. 11/137,901, filed Feb. 6, 2008.
Response to Restriction Requirement from U.S. Appl. No. 11/596,092, filed May 27, 2009.
Restriction Requirement from U.S. Appl. No. 10/918,803, mailed on Jun. 12, 2009.
Restriction Requirement from U.S. Appl. No. 10/918,803, mailed on Mar. 13, 2007.
Restriction Requirement from U.S. Appl. No. 10/918,803, mailed on Sep. 7, 2007.
Restriction Requirement from U.S. Appl. No. 11/110,204, mailed on Mar. 10, 2008.
Restriction Requirement from U.S. Appl. No. 11/129,006, mailed on Nov. 12, 2008.
Restriction Requirement from U.S. Appl. No. 11/137,901, mailed on Aug. 6, 2007.
Restriction Requirement from U.S. Appl. No. 11/137,901, mailed on May 23, 2008.
Restriction Requirement from U.S. Appl. No. 11/596,092, mailed on Jan. 28, 2009.
Restriction Requirement from U.S. Appl. No. 11/884,566, mailed on Apr. 5, 2010.
Restriction Requirement mailed on Dec. 1, 2011, for U.S. Appl. No. 13/163,597, filed Jun. 17, 2011, 7 pages.
Restriction Requirement mailed on Feb. 9, 2012, for U.S. Appl. No. 12/618,612, filed Nov. 13, 2009, 7 pages.
Restriction Requirement mailed on Jun. 7, 2012, for U.S. Appl. No. 13/399,828, filed Feb. 17, 2012, 5 pages.
Restriction Requirement mailed on Oct. 14, 2010, for U.S. Appl. No. 12/732,124, filed Mar. 25, 2010, 9 pages.
Reyes et al., J. Clin. Invest. (2002) 109:337-346.
Rickert et al., Trends Cell Biol. (2000) 10:466-473.
Riesterer, Int'l J Radiation Oncology Biology Physics (2004) 361-368.
Roberts et al., Immunity (1999) 10:183-196.
Rodrigues et al., Mol. Cell. Biol. (2000) 20:1448-1459.
Rodriguez-Viciana et al., EMBO J. (1996) 15:2442-2451.
Roth et al., J. Immunol. Methods (1995) 188:97-116.
Rowlinson-Busza et al., Curr. Opin. Oncol.(1992) 4:1142-1148.
Rudd, Immunity (1996) 4:527-534.
Rupnick et al., Proc. Nat'l. Acad. Sci. (USA) (2002) 99:10730-35.
Sadhu et al., J. Immunol. (2003) 170:2647-2654.
Sakamoto et al., Angew. Chem. (2003) 115:4496-4499.
Salven et al., Blood (1999) 94:3334-3339.
Salvesen et al., Cell (1997) 91:443-446.
Sasaki et al., Science (2000) 287:1040-1046.
Sauder et al., J. Am. Acad. Dermatol. (2002) 47:535-541.
Schimmer et al., J. Immunol. (1998) 160:1466-1471.
Schrottner, P. et al. (May 1, 2010). "The Role of Chemokines in B Cell Chronic Lymphocytic Leukaemia: Pathophysiological Aspects and Clinical Impact," Annals of Hematology89(5):437-446.
Schuch et al., Blood (2002) 100:4622-4628.
Schueneman et al., Canc. Res. (2003) 63:4009-4016.
Second Preliminary Amendment and Response to Notice to File Missing Parts of Nonprovisional Application from U.S. Appl. No. 12/575,277, filed Jan. 20, 2010.
Second Preliminary Amendment and Response to Notice to File Missing Parts of Nonprovisional Application from U.S. Appl. No. 12/575,367, filed Jan. 20, 2010.
Second Preliminary Amendment from U.S. Appl. No. 11/110,204, filed Aug. 24, 2007.
Second Preliminary Amendment from U.S. Appl. No. 11/884,566, filed May 13, 2008.
Sengupta et al., Circulation (2003) 107:2955-2961.
Sharman J. et al. (Nov. 2011). "A Phase I Study of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3K Delta) Inhibitor, CAL-101 (GS-1101), in Combination with Rituximab and/or Bendamustine in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)," Blood 118(21):779-780.
Shimamoto et al., Leukemia Res. (2003) 27:783-788.
Shiojima et al., Circ. Res. (2002) 90:1243-1250.
Shvidel et al., Hematol. J. (2002) 3:32-37.
Smith et al., Am. J. Respir. Cell Mol. Biol. (1996) 15(6):693-702.
Song et al., Canc. Res. (1974) 34:2344-2350.
Springer, Cell (1994) 76:301-314.
Stein et al., Mol. Med. Today (2000) 6:347-357.
Stenmark et al., J. Cell. Sci. (1999) 112:4175-4183.
Stennicke et al., Biochim. Biophys. Acta. (2000) 1477:299-306.
Stephens et al., Current Biology (1994) 4:203-214.
Stirewalt et al., Nat. Rev. Cancer (2003) 3:650-665.
Stoyanov et al., Science (1995) 269:690-693.
Su et al., Cancer Research (2003) 63:3585-3592.
Sujobert et al., Blood(2005) 106(3):1063-1066.
Sumariwalla et al., Arthritis Res. Ther. (2002) 5:R32-R39.
Sunil et al., Respir. Res. (2002) 3:21.
Supplemental Amendment from U.S. Appl. No. 11/110,204, filed Oct. 27, 2009.
Supplemental Notice of Allowance from U.S. Appl. No. 10/337,192, mailed on Jun. 29, 2004.
Sutton, a. (Jun. 9, 2006). "Baylor, St. Luke's study uses gene therapy as pancreatic cancer", located at <http: //www.bcm.edu/news/item.cfm%3FnewsID=640>, last visited on Sep. 2, 2006, 2 pages.
Tager et al., J. Exp. Med. (2000) 192:439-446.
Talento et al., Transplantation (1993) 55:418-422.
Tamiya et al., Immunopharmacology (1995) 29:53-63.
Tan et al., Cancer Research (2003) 63:7663-7667.
Tan et al., J. Immunol. Meths. (2000), 238:59-68.
Tan, J. et al. (Sep. 1, 2004). "A Specific Antagonist of the p110-Delta Catalytic Component of P13 Kinase, IC486068, Enhances Radiation-Induced Tumor Vascular Destruction," International Journal of Radiation: Oncology Biology Physics 60(1):S195.
Tanaka et al., J. Immunol. (1993) 151:5088-5095.
Tang et al., J. Biol. Chem. (1999) 274:16741-16746.
Taylor et al., Curr. Opin. Rheumatol. (2005) 17(3):293-298.
Tesar et al., Med. Sc. Monit. (2002) 8:BR24-BR29.
The Merck Manual on "arthritis" (2008).
The Merck Manual on "rheumatoid arthritis" (2008).
The Merck Manual, 17th ed, (1999) p. 1001.
Thelan et al., Proc. Natl. Acad. Sci. (USA) (1994) 91:4960-4964.
Ting et al., Int. J. Rad. Biol. (1991) 60:335-339.
Trail et al., Science(1993) 261:212-215.
U.S. Appl. No. 12/732,124, filed by Fowler et al. on Mar. 25, 2010.
U.S. Appl. No. 12/732,128, filed by Fowler et al. on Mar. 25, 2010.
Vacca et al., Blood (1999) 9:3064-3073.
Van Dijk et al., Blood (2000) 96:3406-3413.
Vanhaesebroeck et al., FASEB J. (1996) 10:A1395, Abst. No. 2280.
Vanhaesebroeck et al., Proc. Natl. Acad. Sci., (USA) (1997) 94:4330-4335.
Vanhaesebroeck et al., TIBS (1997) 22:267-272.
Vippagunta, S.R. et al. (2001). "Crystalline Solids," Advanced Drug Delivery 48:3-26.
Vivanco et al., Nat. Rev. Cancer (2002) 2:489-501.
Vlahos et al., J. Immunol. (1995) 154:2413-2422.
Volinia et al., EMBO J. (1995) 14:3339-3348.
Volinia et al., Genomics (1994) 24:472-477.
Volinia et al., Oncogene (1992) 7:789-793.
Webb, H.K. et al. (Apr. 2009). "CAL-101, a Potent and Selective Inhibitor of the Class 1 Phosphatidylinositol 3 Kinase (PI3K) p110δ: Preclinical Summary," Proceedings of the American Association for Cancer Research 50:894-895, Abstract No. #3703.
Wegner et al., Lung (1992) 170:267-279.
Wegner et al., Science (1990) 247:456-459.
Weiner et al., Nat. Cell Biol. (1999) 1:75-81.
Weyand et al., Arthritis & Rheumatism (2000) 43:1041-1048.
White et al., Bioorganic & Medicinal Chemistry (2004) 12:5711-5717.
Wierda, Hematology(2006) 285-294.
Williams et al., Chemistry & Biology (2010) 17:123-134.
Williams et al., Chemistry & Biology(2010) 17:123-134.
Williams, D.A. et al. (2002). Foye's Principles of Medicinal Chemistry, Lippincott, Williams & Wilkins, Baltimore MD, Fifth Edition, pp. 50 and 59-61.
Williams, Methods Mol. Med. (2004) 98:207-216.
Wolff, ed., Burger's Medicinal Chemistry and Drug Discovery, 5th edition (1996) vol. 1, New York: John Wiley & Sons, pp. 975-977.
Written Opinion mailed on Dec. 5, 2011, for PCT Application No. PCT/US2011/053102, filed on Sep. 23, 2011, 6 pages.
Written Opinion mailed on Jan. 21, 2012 for PCT Application No. PCT/US2010/042801, filed on Jul. 21, 2010, 10 pages.
Written Opinion mailed on Jun. 14, 2012 for PCT Application No. PCT/US2012/028654, filed on Mar. 9, 2012, 11 pages.
Written Opinion of the International Searching Authority for PCT/US2009/064471, Mailed on Feb. 12, 2010, 5 pages.
Wymann et al., Biochem. Biophys. Acta. (1998) 1436:127-150.
Wymann et al., Biochem. J. (1994) 298:517-520.
Wymann et al., Trends Immunol. Today (2000) 21:260-264.
Xing et al., Am. J. Pathol. (1993) 143:1009-1015.
Xu et al., Blood (2003) 102:972-980.
Yamasawa et al., Inflammation (1999) 23:263-274.
Yamaura et al., Int. J. Rad. Biol. (1976) 30:179-187.
Yao et al., Science (1995) 267:2003-2006.
Yum et al., J. Immunol. (2001) 167:6601-6608.
Zeng et al., Transplantation (1994) 58:681-689.
Zhang and Franco, "Method development with CHIRALPAK IA: The new Diacel column with broad solvent versatility" Chiral Technologies Europe, Apr. 2004.
Zhao et al., Leukemia (2004) 18:267-75.

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9518046B2 (en) 2013-09-22 2016-12-13 Calitor Sciences, Llc Substituted aminopyrimidine compounds and methods of use
US9670194B2 (en) 2013-09-22 2017-06-06 Calitor Sciences, Llc Substituted aminopyrimidine compounds and methods of use
US10836759B2 (en) 2016-06-22 2020-11-17 The University Of North Carolina At Chapel Hill Thiazole derivatives useful as mutant IDH1 inhibitors for treating cancer
US10016425B2 (en) 2016-11-03 2018-07-10 King Saud University Anti-ulcerative colitis compound
WO2021207549A1 (en) 2020-04-10 2021-10-14 Gb005, Inc. Kinase inhibitors

Also Published As

Publication number Publication date
IL215251A0 (en) 2011-12-29
AU2010229968A1 (en) 2011-10-13
AP2011005943A0 (en) 2011-10-31
CL2011002359A1 (es) 2012-04-09
EA201171160A1 (ru) 2012-04-30
ECSP11011412A (es) 2012-03-30
KR20120002995A (ko) 2012-01-09
CO6450655A2 (es) 2012-05-31
SG174529A1 (en) 2011-10-28
MX2011009955A (es) 2011-11-18
JP2012521994A (ja) 2012-09-20
BRPI1012333A2 (pt) 2016-03-29
NZ595307A (en) 2013-11-29
WO2010111432A1 (en) 2010-09-30
PE20120602A1 (es) 2012-05-21
EA019499B1 (ru) 2014-04-30
EP2411391A1 (en) 2012-02-01
US20100249155A1 (en) 2010-09-30
CN102439012A (zh) 2012-05-02
CA2756347A1 (en) 2010-09-30

Similar Documents

Publication Publication Date Title
US8440677B2 (en) Atropisomers of 2-purinyl-3-tolyl-quinazolinone derivatives and methods of use
US20130324561A1 (en) Atropisomers of p13k-inhibiting compounds
JP7261428B2 (ja) ピロロピリミジン類化合物及びその使用
AU2015290041A1 (en) Syk inhibitors
CN112105618B (zh) 作为选择性HER2抑制剂的吡咯并[2,1-f][1,2,4]三嗪类衍生物及其应用
JP6244353B2 (ja) ピリジニルピラゾロキノリン化合物
EP3845532B1 (en) Quinolino-pyrrolidin-2-one derivative and application thereof
US20210403451A1 (en) Pyrimidopyrazolone derivative as wee1 inhibitor and use thereof
CN113825757B (zh) 取代的稠合双环类衍生物、其制备方法及其在医药上的应用
CN113614090A (zh) 含有异噻唑烷1,1-二氧化物和1,4-丁烷磺内酯的雷帕霉素衍生物及其用途
US20160060269A1 (en) DOT1L Inhibitors
CN115667258A (zh) 氟代吡咯并吡啶类化合物及其应用
US20230113620A1 (en) Use of jak inhibitors in preparation of drugs for treating jak kinase-related diseases
CN116323579B (zh) 1H-吡咯并[2,3-c]吡啶类化合物及其应用
EP4234558A1 (en) Pyrrolopyridine compound and application thereof
US20240182457A1 (en) Oxadiazole-substituted spirocyclic compound and application thereof
CN115968362A (zh) 作为pet放射性示踪剂的[18f]-标记的咪唑并吡啶衍生物

Legal Events

Date Code Title Description
AS Assignment

Owner name: CALISTOGA PHARMACEUTICALS, INC., WASHINGTON

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:EVARTS, JERRY B.;ULRICH, ROGER G.;REEL/FRAME:024489/0536

Effective date: 20100422

AS Assignment

Owner name: GILEAD CALISTOGA LLC, CALIFORNIA

Free format text: CHANGE OF NAME;ASSIGNOR:CALISTOGA PHARMACEUTICALS, INC.;REEL/FRAME:027606/0185

Effective date: 20110526

FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Free format text: PAYER NUMBER DE-ASSIGNED (ORIGINAL EVENT CODE: RMPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20170514